Kinase inhibitors

ABSTRACT

There are provided compounds of formula I, 
                         
wherein R 1  to R 5 , X 1 , X 2 , Ar, L, E, A, A 1 , G and G 1  have meanings given in the description, which compounds have antiinflammatory activity (e.g. through inhibition of one or more of members of: the family of p38 mitogen-activated protein kinase enzymes; Syk kinase; and members of the Src family of tyrosine kinases) and have use in therapy, including in pharmaceutical combinations, especially in the treatment of inflammatory diseases, including inflammatory diseases of the lung, eye and intestines.

FIELD OF THE INVENTION

This invention relates, inter alia, to compounds which areantiinflammatory agents (e.g. through inhibition of one or more ofmembers of: the family of p38 mitogen-activated protein kinase enzymes(referred to herein as p38 MAP kinase inhibitors), for example the alphakinase sub-type thereof; Syk kinase; and the Src family of tyrosinekinases). The invention also relates to the use of such compounds intherapy, including in mono- and combination therapies, especially in thetreatment of inflammatory diseases, including inflammatory diseases ofthe lung (such as asthma and chronic obstructive pulmonary disease(COPD)), eye (such as uveitis) and gastrointestinal tract (such asCrohn's disease and ulcerative colitis).

BACKGROUND

The listing or discussion of an apparently prior-published document inthis specification should not necessarily be taken as an acknowledgementthat the document is part of the state of the art or is common generalknowledge.

Four p38 MAPK isoforms (alpha, beta, gamma and delta respectively) havebeen identified, each displaying different patterns of tissueexpression. The p38 MAPK alpha and beta isoforms are found ubiquitouslythroughout the body; are present in many different cell types and areinhibited by a number of previously described small molecular weightcompounds. Early classes of inhibitors were highly toxic due to thebroad tissue distribution of these isoforms which resulted in off-targeteffects of the compounds. Some of the more recently identifiedinhibitors show improved selectivity for p38 MAPK alpha and betaisoforms and have wider safety margins.

p38 MAP kinase is believed to play a pivotal role in many of thesignalling pathways that are involved in initiating and maintainingchronic, persistent inflammation in human disease, for example, insevere asthma, COPD and inflammatory bowel disease (IBD). There is nowan abundant literature which demonstrates that p38 MAP kinase isactivated by a range of pro-inflammatory cytokines and that itsactivation results in the recruitment and release of furtherpro-inflammatory cytokines. Indeed, data from some clinical studiesdemonstrate beneficial changes in disease activity in patients duringtreatment with p38 MAP kinase inhibitors. For instance Smith describesthe inhibitory effect of p38 MAP kinase inhibitors on TNFα (but notIL-8) release from human PBMCs (Smith, S. J., Br. J. Pharmacol., 2006,149:393-404).

The use of inhibitors of p38 MAP kinase in the treatment of COPD and IBDhas also been proposed. Small molecule inhibitors targeted to p38MAPKα/β have proved to be effective in reducing various parameters ofinflammation in:

-   -   cells and tissues obtained from patients with COPD, who are        generally corticosteroid insensitive (Smith, S. J., Br. J.        Pharmacol., 2006, 149:393-404);    -   biopsies from IBD patients (Docena, G. et al., J. of Trans.        Immunol., 2010, 162:108-115); and    -   in vivo animal models (Underwood, D. C. et al., Am. J. Physiol.,        2000, 279:L895-902; Nath, P. et al., Eur. J. Pharmacol., 2006,        544:160-167).

Irusen and colleagues also suggested the possibility of involvement ofp38 MAPKα/β on corticosteroid insensitivity via the reduction of bindingaffinity of the glucocorticoid receptor (GR) in nuclei (Irusen, E. etal., J. Allergy Clin. Immunol., 2002, 109:649-657). Clinicalinvestigations in inflammatory diseases with a range of p38 MAP kinaseinhibitors, including AMG548, BIRB 796, VX702, SC10469 and SC10323, hasbeen described (Lee, M. R. and Dominguez, C., Current Med. Chem., 2005,12:2979-2994.). However, the major obstacle hindering the utility of p38MAP kinase inhibitors in the treatment of human chronic inflammatorydiseases has been the toxicity observed in patients. This has beensufficiently severe to result in the withdrawal from clinicaldevelopment of many of the compounds progressed, including all thosespecifically mentioned above.

COPD is a condition in which the underlying inflammation is reported tobe substantially resistant to the anti-inflammatory effects of inhaledcorticosteroids. Consequently, a superior strategy for treating COPDwould be to develop an intervention which has both inherentanti-inflammatory effects and the ability to increase the sensitivity ofthe lung tissues of COPD patients to inhaled corticosteroids. The recentpublication of Mercado et al. (2007; American Thoracic Society AbstractA56) demonstrates that silencing p38 MAPK gamma has the potential torestore sensitivity to corticosteroids. Thus, there may be a dualbenefit for patients in the use of a p38 MAP kinase inhibitor for thetreatment of COPD.

Many patients diagnosed with asthma or with COPD continue to suffer fromuncontrolled symptoms and from exacerbations of their medical conditionthat can result in hospitalisation. This occurs despite the use of themost advanced, currently available treatment regimens, comprising ofcombination products of an inhaled corticosteroid and a long actingβ-agonist. Data accumulated over the last decade indicates that afailure to manage effectively the underlying inflammatory component ofthe disease in the lung is the most likely reason that exacerbationsoccur. Given the established efficacy of corticosteroids asanti-inflammatory agents and, in particular, of inhaled corticosteroidsin the treatment of asthma, these findings have provoked intenseinvestigation. Resulting studies have identified that some environmentalinsults invoke corticosteroid-insensitive inflammatory changes inpatients' lungs. An example is the response arising fromvirally-mediated upper respiratory tract infections (URTI), which haveparticular significance in increasing morbidity associated with asthmaand COPD.

It has been disclosed previously that compounds that inhibit theactivity of both the c-Src and Syk kinases are effective agents againstrhinovirus replication (Charron, C. E. et al., WO 2011/158042) and thatcompounds that inhibit p59-HCK are effective against influenza virusreplication (Charron, C. E. et al., WO 2011/070369). Taken together withinhibition of p38 MAPK, these are particularly attractive properties forcompounds to possess that are intended to treat patients with chronicrespiratory diseases.

Certain p38 MAPK inhibitors have also been described as inhibitors ofreplication of respiratory syncytial virus (Cass L. et al., WO2011/158039).

The precise etiology of IBD is uncertain, but is believed to be governedby genetic and environmental factors that interact to promote anexcessive and poorly controlled mucosal inflammatory response directedagainst components of the luminal microflora. This response is mediatedthrough infiltration of inflammatory neutrophils, dendritic cells andT-cells from the periphery. Due to the ubiquitous expression of p38 ininflammatory cells it has become an obvious target for investigation inIBD models. Studies investigating the efficacy of p38 inhibitors inanimal models of IBD and human biopsies from IBD patients indicated thatp38 could be a target for the treatment of IBD (Hove, T. ten et al.,Gut, 2002, 50:507-512, Docena, G. et al., J. of Trans. Immunol, 2010,162:108-115). However, these findings are not completely consistent withother groups reporting no effect with p38 inhibitors (Malamut G. et al.,Dig. Dis. Sci, 2006, 51:1443-1453). A clinical study in Crohn's patientsusing the p38 alpha inhibitor BIRB796 demonstrated potential clinicalbenefit with an improvement in C-reactive protein levels. However thisimprovement was transient, returning to baseline by week 8 (Schreiber,S. et al., Clin. Gastro. Hepatology, 2006, 4:325-334). A small clinicalstudy investigating the efficacy of CNI-1493, a P38 and Jnk inhibitor,in patients with severe Crohn's disease showed significant improvementin clinical score over 8 weeks (Hommes, D. et al. Gastroenterology. 2002122:7-14).

T cells are known to play key role in mediating inflammation of thegastrointestinal tract. Pioneering work by Powrie and colleaguesdemonstrated that transfer of naive CD4+ cells into severely compromisedimmunodeficient (SCID) animals results in the development of colitiswhich is dependent on the presence of commensal bacteria (Powrie F. etal. Int Immunol. 1993 5:1461-71). Furthermore, investigation of mucosalmembranes from IBD patients showed an upregulation of CD4+ cells whichwere either Th1 (IFNγ/IL-2) or Th2 (IL5/TGFβ) biased depending onwhether the patient had Crohn's disease or ulcerative colitis (Fuss I J.et al. J Immunol. 1996 157:1261-70.). Similarly, T cells are known toplay a key role in inflammatory disorders of the eye with severalstudies reporting increased levels of T cell associated cytokines (IL-17and IL-23) in sera of Behçets patients (Chi W. et al. Invest OphthalmolVis Sci. 2008 49:3058-64). In support, Direskeneli and colleaguesdemonstrated that Behcets patients have increased Th17 cells anddecreased Treg cells in their peripheral blood (Direskeneli H. et al. JAllergy Clin Immunol. 2011 128:665-6).

One approach to inhibit T cell activation is to target kinases which areinvolved in activation of the T cell receptor signalling complex. Sykand Src family kinases are known to play a key role in this pathway,where Src family kinases, Fyn and Lck, are the first signallingmolecules to be activated downstream of the T cell receptor (Barber E K.et al. PNAS 1989 86:3277-81). They initiate the tyrosine phosphorylationof the T cell receptor leading to the recruitment of the Syk familykinase, ZAP-70. Animal studies have shown that ZAP-70 knockout resultsin a SCID phenotype (Chan A C. et al. Science. 1994 10;264(5165):1599-601).

A clinical trial in rheumatoid arthritis patients with the Syk inhibitorFostamatinib demonstrated the potential of Syk as an anti-inflammatorytarget with patients showing improved clinical outcome and reduced serumlevels of IL-6 and MMP-3 (Weinblatt M E. et al. Arthritis Rheum. 200858:3309-18). Syk kinase is widely expressed in cells of thehematopoietic system, most notably in B cells and mature T cells.Through interaction with immunoreceptor tyrosine-based activation (ITAM)motifs it plays an important role in regulating T cell and B cellexpansion as well as mediating immune-receptor signalling ininflammatory cells. Syk activation leads to IL-6 and MMPrelease-inflammatory mediators commonly found upregulated ininflammatory disorders including IBD and rheumatoid arthritis (Wang Y D.et al World J Gastroenterol 2007; 13: 5926-5932, Litinsky I et al.Cytokine. 2006 January 33:106-10).

In addition to playing key roles in cell signalling events which controlthe activity of pro-inflammatory pathways, kinase enzymes are now alsorecognised to regulate the activity of a range of cellular functions,including the maintenance of DNA integrity (Shilo, Y. Nature ReviewsCancer, 2003, 3: 155-168) and co-ordination of the complex processes ofcell division. Indeed, certain kinase inhibitors (the so-called“Olaharsky kinases”) have been found to alter the frequency ofmicronucleus formation in vitro (Olaharsky, A. J. et al., PLoS Comput.Biol., 2009, 5(7)). Micronucleus formation is implicated in, orassociated with, disruption of mitotic processes and is thereforeundesirable. Inhibition of glycogen synthase kinase 3α (GSK3α) was foundto be a particularly significant factor that increases the likelihood ofa kinase inhibitor promoting micronucleus formation. Also, inhibition ofthe kinase GSK3β with RNAi has been reported to promote micronucleusformation (Tighe, A. et al., BMC Cell Biology, 2007, 8:34).

Whilst it may be possible to attenuate the adverse effects of inhibitionof Olaharsky kinases such as GSK3α by optimisation of the dose and/or bychanging the route of administration of a molecule, it would beadvantageous to identify further therapeutically useful molecules withlow or negligible inhibition of Olaharsky kinases, such as GSK 3α and/orhave low or negligible disruption of mitotic processes (e.g. as measuredin a mitosis assay).

Various urea derivatives are disclosed as having anti-inflammatoryproperties (see, for example, WO 01/36403, WO 01/4115, WO 02/092576, WO2003/068228, WO 2003/072569, WO 2004/113352, WO 2007/053394 and Bioorg.Med. Chem. Lett. 2007, 17, 354-357). Nevertheless, there remains a needto identify and develop alternative p38 MAP kinase inhibitors, andparticularly inhibitors that have improved therapeutic potential overcurrently available treatments or, in particular, that exhibit asuperior therapeutic index (e.g. inhibitors that are at least equallyefficacious and, in one or more respects, are less toxic at the relevanttherapeutic dose than previous agents).

SUMMARY OF THE INVENTION

We have now discovered, surprisingly, that certain alkyne-containingdiaryl ureas inhibit one or more of p38 MAP kinase, Syk and Src familykinases and therefore possess good anti-inflammatory properties.

Thus, according to a first aspect of the invention, there is provided acompound of formula I,

wherein

-   R¹ represents H or C₁₋₃ alkyl;-   R² and R³ independently represent H or C₁₋₃ alkyl, or R² and R³    together combine to form C₂₋₃ alkylene;-   X¹ and X² are both N, or X¹ is C and X² is either O or S;

Ar is phenyl or a 5- or 6-membered heteroaryl group containing one ormore heteroatoms selected from N, O and S, which phenyl and heteroarylgroups are optionally substituted by one or more substituents selectedfrom halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, hydroxy, amino andcyano;

L is a direct bond or C₁₋₂ alkylene;

E represents:

-   (a) H, halo, hydroxy, NR^(6a)R^(6b), cyano, C(O)OR^(6c),    C(O)NR^(6d)R^(6e), SH, S(O)_(n)R⁸, S(O)₂NR^(6f)R^(6g),-   (b) C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₈ alkoxy, which    latter four groups are optionally substituted by one or more    substituents selected from halo and NR^(7a)R^(7b),-   (c) C₃₋₈ cycloalkyl, Het¹ or Ar¹, which latter three groups are    optionally substituted by one or more substituents selected from    halo, hydroxy and C₁₋₃ alkyl;    R^(6a) to R^(6g) independently represent H or C₁₋₄ alkyl, or    any one or more of the pairs R^(6a) and R^(6b), R^(6d) and R^(6e),    and R^(6f) and R^(6g), when taken together with the N-atom to which    each pair is attached, form a saturated 4- to 7-membered    heterocyclic group, which heterocyclic group contains one N atom    (the atom to which the pairs of substituents are attached) and,    optionally, one or more further heteroatoms selected from O, S and    N, and which heterocyclic group is optionally substituted by one or    more C₁₋₂ alkyl groups;-   R^(7a) and R^(7b), independently on each occurrence, represent H or    C₁₋₄ alkyl, or, together with the N-atom to which they are attached,    form a 5- to 7-membered heterocyclic group that is fully saturated,    partially unsaturated or fully aromatic and which heterocyclic group    contains one N atom (the atom to which R^(7a) and R^(7b) are    attached) and, optionally, one or more further heteroatoms selected    from O, S and N, and which heterocyclic group is optionally    substituted by one or more substituents selected from halo, hydroxy,    oxo, C₁₋₄ alkyl and C₁₋₄ alkoxy;-   R⁸ represents C₁₋₄ haloalkyl, C₁₋₄ alkyl, C₃₋₈ cycloalkyl or Ar²,    which latter three groups are optionally substituted by one or more    substituents selected from halo, hydroxy and C₁₋₃ alkyl;-   Ar¹ and Ar² independently represent C₆₋₁₄ carbocyclic aryl groups,    which groups may be monocyclic, bicyclic or tricyclic and which    groups contain at least one ring which is fully aromatic,-   n is 0, 1 or 2;-   R⁴ and R⁵ are each independently C₁₋₃ alkyl, C₁₋₃ haloalkyl, cyano    or halo,-   or R⁴ and R⁵ together combine to form C₃₋₅ alkylene or C₃₋₅    alkenylene, which latter two groups are optionally substituted by    one or more substituents selected from C₁₋₃ alkyl, C₁₋₃ haloalkyl,    cyano and halo,-   or R⁴ and R⁵, together with the C-atoms to which they are attached,    form a fused phenyl or Het² ring, which latter two rings are    optionally substituted by one or more substituents selected from    C₁₋₃ alkyl, C₁₋₃ haloalkyl, cyano and halo;-   Het¹ and Het² independently represent 5- to 7-membered heterocyclic    groups that are fully saturated, partially unsaturated or fully    aromatic, which heterocyclic groups contain one or more heteroatoms    selected from N, O and S;-   one of A and A¹ represents N and the other represents CH, or both of    A and A¹ represent CH;-   G represents    -   phenyl optionally substituted by one or more Y¹ or    -   Het³ optionally substituted by one or more Y²;-   G¹ represents H;-   or G and G¹ together combine to form C₃₋₆ alkylene optionally    substituted by one or more substituents selected from halo, hydroxy    and C₁₋₃ alkyl, which latter group is optionally substituted by one    or more halo atoms or by hydroxy;-   each Y¹ is independently selected from the group consisting of    -   halo, hydroxy, cyano, SF₅, —OC(O)NH₂,    -   P(O)R^(9a)R^(9b),    -   J¹-N(R^(9c))R^(9d),    -   J²-S(O)₂R^(9e),    -   J³-[CH₂(CH₂)₀₋₁CH₂—O]₂₋₈—R^(9f),    -   —C≡C—R^(9g),    -   —N═S(O)R^(9h)R^(9i),    -   Het^(a),    -   C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₁₋₆ alkoxy, C₃₋₆ cycloalkoxy,        —S(O)₀₋₁—C₁₋₆ alkyl and —S(O)₀₋₁—C₃₋₆ cycloalkyl which latter        six groups are optionally substituted by one or more        substituents selected from halo, hydroxy, C₁₋₃ alkyl, C₁₋₃        alkoxy and C₃₋₆ cycloalkyl;        each Y² independently represents oxo or Y¹;        J¹ represents    -   a direct bond,    -   —C(O)—    -   —[C(O)]_(p)—C₁₋₈ alkylene,    -   —C(O)NR^(10a)—CH₂—[C₁₋₇ alkylene]-,    -   -Q¹-CH₂—[C₁₋₅ alkylene]-,    -   the alkylene parts of which latter four groups are optionally        substituted by one or more substituents selected from halo, C₁₋₃        alkyl and hydroxy;        J² represents    -   a direct bond,    -   —O—,    -   —NH—    -   C₁₋₆ alkylene or    -   -Q²-CH₂—[C₁₋₅ alkylene]-,    -   the alkylene parts of which latter two groups are optionally        substituted by one or more substituents selected from halo, C₁₋₃        alkyl and hydroxy;-   J³ represents —O— or S(O)₀₋₂;-   Q¹ and Q² independently represent O or S(O)₀₋₂;-   p represents 0 or 1;-   R^(9a) and R^(9b) independently represent C₁₋₃ alkyl or C₁₋₃ alkoxy,    or R^(9a) and R^(9b) together combine to form C₄₋₆ alkylene;-   R^(9c) and R^(9d) independently represent H or C₁₋₈ alkyl, which    latter group is optionally substituted by R^(10b) and/or one or more    substituents selected from halo and hydroxy; or-   R^(9c) and R^(9d), together with the N-atom to which they are    attached, form a 4- to 7-membered heterocyclic group that is fully    saturated, partially unsaturated or fully aromatic and which    heterocyclic group contains one N atom (the atom to which R^(9c) and-   R^(9d) are attached) and, optionally, one or more further    heteroatoms selected from O, S and N, and which heterocyclic group    is optionally substituted by one or more substituents selected from    halo, hydroxy, oxo, C₁₋₄ alkyl and C₁₋₄ alkoxy;-   R^(9e) represents C₁₋₆ alkyl, C₃₋₆ cycloalkyl or phenyl, which    latter three groups are optionally substituted by one or more    substituents selected from halo, hydroxy, C₁₋₃ alkyl, C₁₋₃ alkoxy    and C₃₋₆ cycloalkyl;-   R^(9f), R^(9g), R^(9h) and R^(9i) independently represent C₁₋₄ alkyl    optionally substituted by one or more halo atoms, or R^(9f) and    R^(9g) independently represent H;-   R^(10a) represents H or C₁₋₃ alkyl optionally substituted by one or    more halo atoms;-   R^(10b) represents C₁₋₄ alkoxy, S—C₁₋₄ alkyl, phenyl or Het⁴, which    latter two groups are optionally substituted by one or more    substituents selected from halo, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₁₋₄    alkoxy, hydroxy, amino and cyano;-   Het³ represents a 5- to 10-membered heteroaromatic group, which    group is monocyclic or bicyclic and contains at least one    carbocyclic or heterocyclic ring that is fully aromatic, and which    group contains one or more heteroatoms selected from N, O and S;-   Het⁴ represents a 4- to 10-membered heterocyclic group that is fully    saturated, partially unsaturated or fully aromatic, which    heterocyclic group contains one or more heteroatoms selected from N,    O and S;-   Het^(a) represents a 5- or 6-membered heterocyclic group that is    fully saturated, partially unsaturated or fully aromatic, which    group contains one or more heteroatoms selected from N, O and S, and    which group is optionally substituted by one or more substituents    selected from halo, hydroxy, C₁₋₃ alkyl, C₁₋₃ alkoxy and C₃₋₆    cycloalkyl,-   or a pharmaceutically acceptable salt, solvate or isotopic    derivative thereof,-   which compounds may be referred to hereinafter as “the compounds of    the invention”.

DETAILED DESCRIPTION

Pharmaceutically acceptable salts that may be mentioned include acidaddition salts and base addition salts. Such salts may be formed byconventional means, for example by reaction of a free acid or a freebase form of a compound of formula I with one or more equivalents of anappropriate acid or base, optionally in a solvent, or in a medium inwhich the salt is insoluble, followed by removal of said solvent, orsaid medium, using standard techniques (e.g. in vacuo, by freeze-dryingor by filtration). Salts may also be prepared by exchanging acounter-ion of a compound of formula I in the form of a salt withanother counter-ion, for example using a suitable ion exchange resin.

Examples of pharmaceutically acceptable salts include acid additionsalts derived from mineral acids and organic acids, and salts derivedfrom metals.

For the avoidance of doubt, compounds of formula I may contain thestated atoms in any of their natural or non-natural isotopic forms. Inthis respect, embodiments of the invention that may be mentioned includethose in which:

-   (a) the compound of formula I is not isotopically enriched or    labelled with respect to any atoms of the compound; and-   (b) the compound of formula I is isotopically enriched or labelled    with respect to one or more atoms of the compound.

References herein to an “isotopic derivative” relate to the second ofthese two embodiments. In particular embodiments of the invention, thecompound of formula I is isotopically enriched or labelled (with respectto one or more atoms of the compound) with one or more stable isotopes.Thus, the compounds of the invention that may be mentioned include, forexample, compounds of formula I that are isotopically enriched orlabelled with one or more atoms such as deuterium or the like.

Compounds of formula I may exhibit tautomerism. All tautomeric forms andmixtures thereof are included within the scope of the invention. Inparticular, the invention includes the keto-enol tautomerism existingbetween indolin-2-one and 2-hydroxyindole.

Unless otherwise specified, alkyl groups and alkoxy groups as definedherein may be straight-chain or, when there is a sufficient number (i.e.a minimum of three) of carbon atoms, be branched. Particular alkylgroups that may be mentioned include, for example, methyl, ethyl,n-propyl, iso-propyl, butyl, n-butyl and tert-butyl. Particular alkoxygroups that may be mentioned include, for example, methoxy, ethoxy,propoxy, and butoxy.

Unless otherwise specified, cycloalkyl groups as defined herein may,when there is a sufficient number (i.e. a minimum of four) of carbonatoms, be part cyclic/acyclic.

Unless otherwise specified, alkylene groups as defined herein may bestraight-chain or, when there is a sufficient number (i.e. a minimum oftwo) of carbon atoms, be branched.

In particular embodiments of the invention, alkylene refers tostraight-chain alkylene.

Unless otherwise stated, the point of attachment of aryl groups may bevia any atom of the ring system. However, when aryl groups are bicyclicor tricyclic, they are linked to the rest of the molecule via anaromatic ring. C₆₋₁₄ aryl groups include phenyl, naphthyl and the like.Embodiments of the invention that may be mentioned include those inwhich aryl is phenyl.

Values of Het^(a) that may be mentioned include imidazolyl (e.g.imidazol-2-yl), isothiazolyl (e.g. isothiazol-3-yl), isoxazolyl (e.g.isoxazol-3-yl), 1,2,4-oxadiazolyl (e.g. 1,2,4-oxadiazol-3-yl or1,2,4-oxadiazol-5-yl), 1,3,4-oxadiazolyl, oxazolyl (e.g. oxazol-2-yl),pyridinyl (e.g. pyridin-2-yl), pyrimidinyl (e.g. pyrimidin-2-yl),1,2,4-thiadiazolyl (e.g. 1,2,4-thiadiazol-3-yl or1,2,4-thiadiazol-5-yl), 1,3,4-thiadiazolyl, thiazolyl (e.g.thiazol-2-yl), 1,2,3-triazolyl (e.g. 1,2,3-triazol-1-yl,1,2,3-triazol-4-yl or 1,2,3-triazol-5-yl) and 1,2,4-triazolyl (e.g.1,2,4-triazol-1-yl, 1,2,4-triazol-3-yl or 1,2,4-triazol-5-yl).

Unless otherwise specified, the term “halo” includes references tofluoro, chloro, bromo or iodo, in particular to fluoro, chloro or bromo,especially fluoro or chloro.

Embodiments of the invention that may be mentioned include those inwhich one or more of the following definitions apply to the compound offormula I:

-   R¹ represents C₁₋₂ alkyl or, particularly, H;-   R² and R³ independently represent C₁₋₂ alkyl, or R² and R³ together    combine to form C₂ alkylene;-   X¹ and X² are both N;-   Ar is pyrimidinyl or, particularly, phenyl or pyridinyl, which three    groups are optionally substituted by one or more substituents    selected from halo, C₁₋₃ alkyl and C₁₋₃ alkoxy;-   L is a direct bond;-   E represents H, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl or C₁₋₆    alkoxy, which latter four groups are optionally substituted by one    or more halo substituents or by NR^(7a)R^(7b),-   R^(7a) and R^(7b), independently on each occurrence, represent C₁₋₂    alkyl, or, together with the N-atom to which they are attached, form    a 5- or 6-membered heterocyclic group that is fully saturated and    which heterocyclic group contains one N atom (the atom to which    R^(7a) and R^(7b) are attached) and, optionally, one further    heteroatom selected from O, S and N, and which heterocyclic group is    optionally substituted by one or more substituents selected from    halo, hydroxy, oxo, C₁₋₄ alkyl and C₁₋₄ alkoxy;-   R⁴ and R⁵ are each independently cyano or halo,-   or R⁴ and R⁵, together with the C-atoms to which they are attached,    form a fused phenyl or Het² ring;-   Het² represents a 6-membered heteroaromatic group containing one or    two N atoms;-   A represents N or CH and A¹ represents CH;-   G represents    -   phenyl optionally substituted by one or more Y¹ or    -   Het³ optionally substituted by one or more Y²;-   each Y¹ is independently selected from the group consisting of halo,    hydroxy, cyano, P(O)R^(9a)R^(9b), —C≡C—H, J¹-N(R^(9c))R^(9d),    —O—[CH₂CH₂O]₂₋₇—R^(9f), —S—C₁₋₄ alkyl, —S—C₁₋₄ alkyl and C₁₋₄    alkoxy, which latter three groups are optionally substituted by    hydroxy or by one or more halo atoms (e.g. each Y¹ is independently    selected from the group consisting of halo, hydroxy, cyano,    P(O)R^(9a)R^(9b), J¹-N(R^(9c))R^(9d), —O—[CH₂CH₂O]₂₋₇—R^(9f),    —S—C₁₋₄ alkyl, —S—C₁₋₄ alkyl and C₁₋₄ alkoxy, which latter three    groups are optionally substituted by hydroxy or by one or more halo    atoms);-   G¹ represents H;-   each Y² is independently oxo or Y¹;-   J¹ represents    -   a direct bond,    -   —C(O)—,    -   C₁₋₄ alkylene,    -   —C(O)NH—CH₂—[C₁₋₃ alkylene]-,    -   -Q¹-CH₂—[C₁₋₃ alkylene]-,    -   the alkylene parts of which latter three groups are optionally        substituted by or by one or more substituents selected from halo        and hydroxy;-   R^(9a) and R^(9b) independently represent C₁₋₃ alkyl (e.g. methyl),    or R^(9a) and R^(9b) together combine to form C₄₋₅ alkylene;-   R⁹ and R^(9d), independently on each occurrence, represent H or C₁₋₄    alkyl, which latter group is optionally substituted by one or more    substituents selected from halo and hydroxy, or    together with the N-atom to which they are attached, R^(9c) and    R^(9c) form a 4- to 7-membered heterocyclic group that is fully    saturated, partially unsaturated or fully aromatic and which    heterocyclic group contains one N atom (the atom to which R^(9c) and    R^(9d) are attached) and, optionally, one or more further    heteroatoms selected from O, S and N, and which heterocyclic group    is optionally substituted by one or more substituents selected from    halo, hydroxy, oxo, C₁₋₄ alkyl and C₁₋₄ alkoxy;-   R^(9f) represents H or C₁₋₂ alkyl;-   Het³ represents a 5- to 10-membered heteroaromatic group, which    group is monocyclic or bicyclic and contains at least one    carbocyclic or heterocyclic ring that is fully aromatic, and which    group contains one to four heteroatoms selected from N, O and S.

Further embodiments of the invention that may be mentioned include thosein which the compound of formula I is a compound of formula Ia,

wherein

-   R¹ represents C₁₋₂ alkyl or, particularly, H;-   R² and R³ independently represent H or C₁₋₂ alkyl, or R² and R³    together combine to form C₂ alkylene;-   A represents CH or N;-   A² represents N or, particularly, CH;-   R⁴ and R⁵ are both halo,-   or R⁴ and R⁵, together with the C-atoms to which they are attached,    form a fused phenyl ring;-   R^(a) represents C₁₋₂ alkoxy or, particularly, C₁₋₂ alkyl, which    latter two groups are optionally substituted by one or more halo    atoms, or R^(a) represents C₁₋₂ alkyl or C₂ alkoxy, which latter two    groups are substituted by NR^(7a)R^(7b);-   R^(7a) and R^(7b) both represent C₁₋₂ alkyl or, together with the    N-atom to which they are attached, form a 5- or 6-membered    heterocyclic group that is fully saturated and which heterocyclic    group contains one N atom (the atom to which R^(7a) and R^(7b) are    attached) and, optionally, one further heteroatom selected from O, S    and N, and which heterocyclic group is optionally substituted by one    or more substituents selected from halo, hydroxy, oxo, C₁₋₄ alkyl    and C₁₋₄ alkoxy;-   A³ and A⁴ both represent CH, or one of A³ and A⁴ represents N and    the other represents CH;-   R^(b), R^(c) and R^(d) independently represent H, halo, hydroxy,    —C≡C—H, C₁₋₄ alkylene-N(R^(9c))R^(9d), —C(O)NH—CH₂—[C₁₋₃    alkylene]-N(R^(9c))R^(9d), -Q¹-CH₂—[C₁₋₃ alkylene]-N(R^(9c))R^(9d),    —O—[CH₂CH₂O]₂₋₇—R^(9f), C₁₋₄ alkyl, C₁₋₄ alkoxy or C(O)NHCl₁₋₄    alkyl, which latter three groups are optionally substituted by one    or more halo atoms (e.g. one of R^(b), R^(c) and R^(d) represents H,    —C(O)NH—CH₂—[C₁₋₃ alkylene]-N(R^(9c))R^(9d) or -Q¹-CH₂—[C₁₋₃    alkylene]-N(R^(9c))R^(9d), and the other two of R^(b), R^(c) and    R^(d) represent H, halo, —C≡C—H, C₁₋₄ alkyl or C₁₋₄ alkoxy, which    latter two groups are optionally substituted by one or more halo    atoms), (for example, R^(b), R^(c) and R^(d) independently represent    H, halo, hydroxy, C₁₋₄ alkylene-N(R^(9c))R^(9d), —C(O)NH—CH₂—[C₁₋₃    alkylene]-N(R^(9c))R^(9d), -Q¹-CH₂—[C₁₋₃ alkylene]-N(R^(9c))R^(9d),    —O—[CH₂CH₂O]₂₋₇—R^(9f), C₁₋₄ alkyl, C₁₋₄ alkoxy or C(O)NHCl₁₋₄    alkyl, which latter three groups are optionally substituted by one    or more halo atoms (e.g. one of R^(b), R^(c) and R^(d) represents H,    —C(O)NH—CH₂—[C₁₋₃ alkylene]-N(R^(9c))R^(9d) or -Q¹-CH₂—[C₁₋₃    alkylene]-N(R^(9c))R^(9d), and the other two of R^(b), R^(c) and    R^(d) represent H, halo, C₁₋₄ alkyl or C₁₋₄ alkoxy, which latter two    groups are optionally substituted by one or more halo atoms)),    or R^(b) and R^(c), together with the C-atoms to which they are    attached, form a fused, 5- or 6-membered heteroaromatic or    heterocyclic ring, which ring:-   (i) contains one to three heteroatoms selected from N, O and S; and-   (ii) is optionally substituted by one or more substituents selected    from H, halo, hydroxy, oxo, amino, C₁₋₂ alkyl and C₁₋₂ alkoxy, which    latter two groups are optionally substituted by one or more halo    atoms;    R⁹ and R^(9d) both represent C₁₋₂ alkyl or, together with the N-atom    to which they are attached, form a 5- or 6-membered heterocyclic    group that is fully saturated and which heterocyclic group contains    one N atom (the atom to which R^(9c) and R^(9d) are attached) and,    optionally, one further heteroatom selected from O, S and N, and    which heterocyclic group is optionally substituted by one or more    substituents selected from halo, hydroxy, oxo, C₁₋₄ alkyl and C₁₋₄    alkoxy; and-   R^(9f) represents H or, particularly, methyl,    or a pharmaceutically acceptable salt, solvate or isotopic    derivative thereof.

Still further embodiments of the invention that may be mentioned includethose in which the compound of formula Ia is a compound of formula Ib,

or a pharmaceutically acceptable salt, solvate or isotopic derivativethereof,wherein R¹ to R⁵, A, A², A³, A⁴, R^(a) to R^(d) are as defined above inrespect of compounds of formula Ia.

Embodiments of the invention that may be mentioned include those inwhich, in the compound of formula Ia or Ib:

-   (1) R^(b) to R^(d) all represent H (e.g. when A represents CH);-   (2) R^(b) is H and R^(c) and R^(d) independently represent H, halo,    —C≡C—H, C₁₋₄ alkylene-N(R^(9c))R^(9d), —C(O)NH—CH₂—[C₁₋₃    alkylene]-N(R^(9c))R^(9d), -Q¹-CH₂—[C₁₋₃ alkylene]-N(R^(9c))R^(9d),    —O—[CH₂CH₂O]₂₋₇—CH₃, C₁₋₄ alkyl, C₁₋₄ alkoxy, C(O)NHCl₁₋₄ alkyl,    which latter three groups are optionally substituted by one or more    halo atoms    -   (e.g. R^(b) represents H, R^(c) represents H, halo, —C≡C—H, C₁₋₄        alkyl or C₁₋₄ alkoxy, which latter two groups are optionally        substituted by one or more halo atoms, and R^(d) represents        —C(O)NH—CH₂CH₂—N(R^(9c))R^(9d), -Q¹-CH₂CH₂—N(R^(9c))R^(9d) or        —O—[CH₂CH₂O]₂₋₇—CH₃)    -   (for example, R^(b) is H and R^(c) and R^(d) independently        represent H, halo, C₁₋₄ alkylene-N(R^(9c))R^(9d),        —C(O)NH—CH₂—[C₁₋₃ alkylene]-N(R^(9c))R^(9d),        -Q¹-CH₂—[C₁₋₃alkylene]-N(R^(9c))R^(9d), —O—[CH₂CH₂O]₂₋₇—CH₃,        C₁₋₄ alkyl, C₁₋₄ alkoxy, C(O)NHC₁₋₄ alkyl, which latter three        groups are optionally substituted by one or more halo atoms    -   (e.g. R^(b) represents H, R^(c) represents H, halo, C₁₋₄ alkyl        or C₁₋₄ alkoxy, which latter two groups are optionally        substituted by one or more halo atoms, and R^(d) represents        —C(O)NH—CH₂CH₂—N(R^(9c))R^(9d), -Q¹-CH₂CH₂—N(R^(9c))R^(9d) or        —O—[CH₂CH₂O]₂₋₇—CH₃)); or-   (3) R^(d) is H, halo, or C₁₋₄ alkyl, which latter group is    optionally substituted by one or more halo atoms, and R^(b) and    R^(c), together with the C-atoms to which they are attached, form a    fused, 5- or 6-membered (e.g. 5-membered) heteroaromatic or    heterocyclic ring, which ring:    -   (i) contains one to three (e.g. one or two) heteroatoms selected        from N, O and S (such as one or two N atoms); and    -   (ii) is optionally substituted by one or more substituents        selected from H, halo, hydroxy, oxo, amino, C₁₋₂ alkyl and C₁₋₂        alkoxy (e.g. selected from H, oxo and C₁₋₂ alkyl), which latter        two groups are optionally substituted by one or more halo atoms.

Further embodiments of the invention that may be mentioned include thosein which one or more of the following definitions apply to the compoundof formula Ia or Ib:

-   (1) R¹ is H;-   (2) R² and R³ represent H or, particularly, methyl;-   (3) R⁴ and R⁵ are both chloro or, together with the C-atoms to which    they are attached, form a fused phenyl ring;-   (4) A² represents CH;-   (5) R^(a) represents methyl;-   (6) A³ represents CH or N and A⁴ represents CH;-   (7) either    -   (i) R^(b), R^(c) and R^(d) are all H,    -   (ii) R^(b) and R^(c) are H and R^(d) represents        —O—CH₂CH₂—N(R^(9c))R^(9d)    -   (iii) one of R^(b), R^(c) and R^(d) is C₁₋₂        alkylene-N(R^(9c))R^(9d), —O—CH₂CH₂—N(R^(9c))R^(9d),        —C(O)NH—CH₂CH₂—N(R^(9c))R^(9d) or —O—[CH₂CH₂O]₂₋₇—CH₃, and the        other two of R^(b), R^(c) and R^(d) are selected from H, —C≡C—H,        C₁₋₂ alkyl and C₁₋₂ alkoxy, which latter two groups are        optionally substituted by one or more halo atoms        -   (e.g. one of R^(b), R^(c) and R^(d) is C₁₋₂            alkylene-N(R^(9c))R^(9d), —O—CH₂CH₂—N(R^(9c))R^(9d),            —C(O)NH—CH₂CH₂—N(R^(9c))R^(9d) or —O—[CH₂CH₂O]₂₋₇—CH₃, and            the other two of R^(b), R^(c) and R^(d) are selected from H,            C₁₋₂ alkyl and C₁₋₂ alkoxy, which latter two groups are            optionally substituted by one or more halo atoms), or    -   (iv) R^(d) is H or methyl and R^(b) and R^(c), together with the        C-atoms to which they are attached and optional substituents        thereon, form a fused ring selected from pyrrolidinone and        pyrazole;-   (7) NR^(9c)R^(9d) represents dimethylamino or morpholin-4-yl.

Particular embodiments of the compounds of formula I, la and Ib that maybe mentioned include those in which the structural fragment

represents a group selected from:

wherein R^(c) and R^(d) are as defined above in respect of compounds offormula Ia or Ib (such as wherein R^(c) and R^(d) are both H), and A^(x)represents N or, particularly, CH.

In this regard, particular embodiments of the invention that may bementioned include those in which the compound of formula I, la or Ib isa compound of formula Ic, Id or Ie,

or a pharmaceutically acceptable salt, solvate or isotopic derivativethereof,wherein

-   R¹ to R⁵, A, A², A^(x) and R^(a) are as defined above in respect of    compounds of formula Ia and Ib;-   R^(c2) and R^(d2) are defined above for R^(c) and R^(d) in respect    of compounds of formula Ia and Ib; and-   R^(d1) is as defined above for R^(d) in respect of compounds of    formula Ia and Ib (e.g. R^(d1) is methyl).

Embodiments of the invention that may be mentioned include those inwhich one or more of the following definitions apply to the compound offormula Ic, Id or Ie:

-   (1) R¹ is H;-   (2) R² and R³ represent H or, particularly, methyl;-   (3) R⁴ and R⁵, together with the C-atoms to which they are attached,    form a fused phenyl ring;-   (3) A² represents CH;-   (4) R^(a) represents methyl;-   (5) A^(x) represents N or, particularly, CH;-   (6) R^(d1) represents H or, particularly, methyl;-   (7) R^(c2) represents H, methyl, trifluoromethyl, —C≡C—H,    trifluoromethoxy or methoxy (e.g. H, methoxy or trifluoromethoxy)    -   (for example, R^(c2) represents trifluoromethyl,        trifluoromethoxy or, particularly, H, methyl, or methoxy (such        as H or methoxy));-   (8) R^(d2) represents methoxy, ethoxy, or, particularly, H,    —C(O)NH—CH₂CH₂—N(R^(9c))R^(9d), —O—[CH₂CH₂O]₂₋₇—CH₃ or    —O—CH₂CH₂—N(R^(9c))R^(9d)(for example, R^(d2) represents methoxy,    ethoxy, —O—[CH₂CH₂O]₂₋₇—CH₃ or, particularly, H,    —C(O)NH—CH₂CH₂—N(R^(9c))R^(9d) or —O—CH₂CH₂—N(R^(9c))R^(9d) (such as    H or —O—CH₂CH₂—N(R^(9c))R^(9d)));-   (9) NR^(9c)R^(9d) represents dimethylamino or morpholin-4-yl.

Particular embodiments that may be mentioned therefore include compoundsof formula Id as hereinbefore defined, but in which:

-   (i) R^(c2) represents H and R^(d2) represents —O—[CH₂CH₂O]₂₋₇—CH₃,    —C(O)NH—CH₂CH₂—N(R^(9c))R^(9d) or, particularly,    —O—CH₂CH₂—N(R^(9c))R^(9d),-   (ii) both of R^(c2) and R^(d2) represent H, or-   (iii) R^(c2) represents CH₃, —C≡C—H, —CF₃, —OCF₃ or —OCH₃ (e.g. CH₃,    —CF₃, —OCF₃ or, particularly, —OCH₃) and R^(d2) represents    —C(O)NH—CH₂CH₂—N(R^(9c))R^(9d), —O [CH₂CH₂O]₂₋₇—CH₃ or    —O—CH₂CH₂—N(R^(9c))R^(9d) (e.g. —O—[CH₂CH₂O]₂₋₇—CH₃ or,    particularly, —C(O)NH—CH₂CH₂—N(R^(9c))R^(9d) or    —O—CH₂CH₂—N(R^(9c))R^(9d)).

Other compounds of formula I, Ia, Ib, Ic, Id or Ie that may be mentionedinclude the compounds of the examples described hereinafter. Thus,embodiments of the invention that may be mentioned include those inwhich the compound of formula I, Ia, Ib, Ic, Id or Ie is a compoundselected from the list:

-   1-(3-(2-methylbut-3-yn-2-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-(phenylamino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea;-   1-(4-((2-((7-methyl-1H-indazol-5-yl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)-3-(3-(2-methylbut-3-yn-2-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)urea;-   1-(3-(2-methylbut-3-yn-2-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((2-oxoindolin-6-yl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea;-   3-methoxy-5-((4-((4-(3-(3-(2-methylbut-3-yn-2-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-N-(2-morpholinoethyl)benzamide;-   1-(3-(2-methylbut-3-yn-2-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((3-(2-morpholinoethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea;-   1-(4-((2-((3-(2-(dimethylamino)ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)-3-(3-(2-methylbut-3-yn-2-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)urea;-   1-(3-(2-methylbut-3-yn-2-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-(phenylamino)pyridin-4-yl)oxy)naphthalen-1-yl)urea;-   1-(4-((2-((3-methoxy-5-(2-morpholinoethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)-3-(3-(2-methylbut-3-yn-2-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)    urea;-   1-(2,3-dichloro-4-((2-((7-methyl-1H-indazol-5-yl)amino)pyrimidin-4-yl)oxy)phenyl)-3-(3-(2-methylbut-3-yn-2-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)urea;-   1-(4-((2-((6-(2-(dimethylamino)ethoxy)pyridin-2-yl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)-3-(3-(2-methylbut-3-yn-2-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)urea;-   1-(4-((2-((4-(2-(dimethylamino)ethoxy)pyridin-2-yl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)-3-(3-(2-methylbut-3-yn-2-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)urea;-   3-((4-((4-(3-(3-(2-methylbut-3-yn-2-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-N-(2-morpholinoethyl)-5-(trifluoromethyl)benzamide;-   1-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)-3-(3-(2-methylbut-3-yn-2-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)    urea;-   3-((4-((4-(3-(3-(2-methylbut-3-yn-2-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-N-(2-morpholinoethyl)-5-(trifluoromethoxy)benzamide;-   3-ethynyl-5-((4-((4-(3-(3-(2-methylbut-3-yn-2-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)    naphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-N-(2-morpholinoethyl)benzamide;-   1-(3-(2-methylbut-3-yn-2-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((6-(2-morpholinoethoxy)    pyridin-2-yl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea; and-   1-(4-((2-((6-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)pyridin-2-yl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)-3-(3-(2-methylbut-3-yn-2-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)    urea,-   or a pharmaceutically acceptable salt, solvate or isotopic    derivative thereof.

Examples of salts of compounds of formula I, Ia, Ib, Ic, Id or Ieinclude all pharmaceutically acceptable salts, such as, withoutlimitation, acid addition salts of strong mineral acids such as HCl andHBr salts and addition salts of strong organic acids such asmethanesulfonic acid.

References herein to a compound of the invention (a compounds of formulaI, Ia, Ib, Ic, Id or Ie) are intended to include references to thecompound and to all pharmaceutically acceptable salts, solvates and/ortautomers of said compound, unless the context specifically indicatesotherwise. In this respect, solvates that may be mentioned includehydrates.

The compounds of the invention (compounds of formula I, Ia, Ib, Ic, Idor Ie) are p38 MAP kinase inhibitors (especially of the alpha subtype)and are therefore useful in medicine, in particular for the treatment ofinflammatory diseases. Further aspects of the invention that may bementioned therefore include the following.

-   (a) A pharmaceutical formulation comprising compound of formula I,    Ia, Ib, Ic, Id or Ie, as hereinbefore defined, or pharmaceutically    acceptable salt, solvate or isotopic derivative thereof, in    admixture with a pharmaceutically acceptable adjuvant, diluent or    carrier.-   (b) A combination product comprising    -   (A) a compound of formula I, Ia, Ib, Ic, Id or Ie, as        hereinbefore defined, or pharmaceutically acceptable salt,        solvate or isotopic derivative thereof, and    -   (B) another therapeutic agent,    -   wherein each of components (A) and (B) is formulated in        admixture with a pharmaceutically-acceptable adjuvant, diluent        or carrier.    -   In this aspect of the invention, the combination product may be        either a single (combination) pharmaceutical formulation or a        kit-of-parts.    -   Thus, this aspect of the invention encompasses a pharmaceutical        formulation including a compound of formula I, Ia, Ib, Ic, Id or        Ie, as hereinbefore defined, or pharmaceutically acceptable        salt, solvate or isotopic derivative thereof, and another        therapeutic agent, in admixture with a pharmaceutically        acceptable adjuvant, diluent or carrier (which formulation is        hereinafter referred to as a “combined preparation”).    -   It also encompasses a kit of parts comprising components:    -   (i) a pharmaceutical formulation including a compound of formula        I, Ia, Ib, Ic, Id or Ie, as hereinbefore defined, or        pharmaceutically acceptable salt, solvate or isotopic derivative        thereof, in admixture with a pharmaceutically acceptable        adjuvant, diluent or carrier; and    -   (ii) a pharmaceutical formulation including another therapeutic        agent, in admixture with a pharmaceutically-acceptable adjuvant,        diluent or carrier,    -   which components (i) and (ii) are each provided in a form that        is suitable for administration in conjunction with the other.    -   Component (i) of the kit of parts is thus component (A) above in        admixture with a pharmaceutically acceptable adjuvant, diluent        or carrier. Similarly, component (ii) is component (B) above in        admixture with a pharmaceutically acceptable adjuvant, diluent        or carrier.-   (c) A process for preparing the pharmaceutical formulation of    aspect (a) above, sad process comprising the step of admixing the    compound of formula I, Ia, Ib, Ic, Id or Ie, as hereinbefore    defined, or pharmaceutically acceptable salt, solvate or isotopic    derivative thereof, with a pharmaceutically acceptable adjuvant,    diluent or carrier.    -   Embodiments of this aspect of the invention that may be        mentioned include those in which the pharmaceutically acceptable        adjuvant, diluent or carrier is a topically acceptable adjuvant,        diluent or carrier (and/or wherein the process is for preparing        a topical pharmaceutical formulation, i.e. a pharmaceutical        formulation that is adapted for topical administration).-   (d) A compound of formula I, Ia, Ib, Ic, Id or Ie, as hereinbefore    defined, or pharmaceutically acceptable salt, solvate or isotopic    derivative thereof, for use in medicine (or for use as a medicament    or as a pharmaceutical).-   (e) A compound of formula I, Ia, Ib, Ic, Id or Ie, as hereinbefore    defined, or pharmaceutically acceptable salt, solvate or isotopic    derivative thereof, or a pharmaceutical formulation or combination    product as defined in connection with aspect (a) or (b) of the    invention, for use in the treatment or prevention of an inflammatory    disease.-   (f) The use of    -   a compound of formula I, Ia, Ib, Ic, Id or Ie, as hereinbefore        defined, or pharmaceutically acceptable salt, solvate or        isotopic derivative thereof, or    -   a pharmaceutical formulation or combination product as defined        in connection with aspect (a) or (b) of the invention, for the        preparation of a medicament for the treatment or prevention of        an inflammatory disease.-   (g) A method of treating or preventing an inflammatory disease, said    method comprising administering to a subject an effective amount of    -   a compound of formula I, Ia, Ib, Ic, Id or Ie, as hereinbefore        defined, or pharmaceutically acceptable salt, solvate or        isotopic derivative thereof, or    -   a pharmaceutical formulation or combination product as defined        in connection with aspect (a) or (b) of the invention.-   (h) A method of sensitizing a subject to the anti-inflammatory    effects of a corticosteroid, said method comprising administering to    the subject an effective amount of    -   a compound of formula I, Ia, Ib, Ic, Id or Ie, as hereinbefore        defined, or pharmaceutically acceptable salt, solvate or        isotopic derivative thereof, or    -   a pharmaceutical formulation or combination product as defined        in connection with aspect (a) or (b) of the invention.    -   Embodiments of this aspect of the invention that may be        mentioned include those in which the subject is one who has        become refractory to the anti-inflammatory effects of a        corticosteroid.        Formulations

In relation to aspects (a) and (b) above, diluents and carriers that maybe mentioned include those suitable for parenteral, oral, topical,mucosal and rectal administration.

The pharmaceutical formulations and combination products of aspects (a)and (b) above may be prepared e.g. for parenteral, subcutaneous,intramuscular, intravenous, intra-articular, intravitreous, periocular,retrobulbar, subconjunctival, sub-Tenon, topical ocular orperi-articular administration, particularly in the form of liquidsolutions, emulsions or suspensions; for oral administration,particularly in the form of tablets or capsules, and especiallyinvolving technologies aimed at furnishing colon-targeted drug release(Patel, M. M. Expert Opin. Drug Deliv. 2011, 8 (10), 1247-1258); fortopical e.g. pulmonary or intranasal administration, particularly in theform of powders, nasal drops or aerosols and transdermal administration;for topical ocular administration, particularly in the form ofsolutions, emulsions, suspensions, ointments, implants/inserts, gels,jellies or liposomal microparticle formulations (Ghate, D.; Edelhauser,H. F. Expert Opin. Drug Deliv. 2006, 3 (2), 275-287); for ocularadministration, particularly in the form of biodegradable andnon-biodegradable implants, liposomes and nanoparticles (Thrimawithana,T. R. et al. Drug Discov. Today 2011, 16 (5/6), 270-277); for mucosaladministration e.g. to buccal, sublingual or vaginal mucosa, and forrectal administration e.g. in the form of a suppository or enema.

The pharmaceutical formulations and combination products of aspects (a)and (b) above may conveniently be administered in unit dosage form andmay be prepared by any of the methods well-known in the pharmaceuticalart, for example as described in Remington's Pharmaceutical Sciences,17th ed., Mack Publishing Company, Easton, Pa., (1985). Formulations forparenteral administration may contain as excipients sterile water orsaline, alkylene glycols such as propylene glycol, polyalkylene glycolssuch as polyethylene glycol, oils of vegetable origin, hydrogenatednaphthalenes and the like. Formulations for nasal administration may besolid and may contain excipients, for example, lactose or dextran, ormay be aqueous or oily solutions for use in the form of nasal drops ormetered sprays. For buccal administration typical excipients includesugars, calcium stearate, magnesium stearate, pregelatinated starch, andthe like.

Pharmaceutical formulations and combination products suitable for oraladministration may comprise one or more physiologically compatiblecarriers and/or excipients and may be in solid or liquid form. Tabletsand capsules may be prepared with binding agents, for example, syrup,acacia, gelatin, sorbitol, tragacanth, or poly-vinylpyrollidone;fillers, such as lactose, sucrose, corn starch, calcium phosphate,sorbitol, or glycine; lubricants, such as magnesium stearate, talc,polyethylene glycol, or silica; and surfactants, such as sodium laurylsulfate. Liquid compositions may contain conventional additives such assuspending agents, for example sorbitol syrup, methyl cellulose, sugarsyrup, gelatin, carboxymethyl-cellulose, or edible fats; emulsifyingagents such as lecithin, or acacia; vegetable oils such as almond oil,coconut oil, cod liver oil, or peanut oil; preservatives such asbutylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT).Liquid compositions may be encapsulated in, for example, gelatin toprovide a unit dosage form.

Solid oral dosage forms include tablets, two-piece hard shell capsulesand soft elastic gelatin (SEG) capsules.

A dry shell formulation typically comprises of about 40% to 60% w/wconcentration of gelatin, about a 20% to 30% concentration ofplasticizer (such as glycerin, sorbitol or propylene glycol) and about a30% to 40% concentration of water. Other materials such aspreservatives, dyes, opacifiers and flavours also may be present. Theliquid fill material comprises a solid drug that has been dissolved,solubilized or dispersed (with suspending agents such as beeswax,hydrogenated castor oil or polyethylene glycol 4000) or a liquid drug invehicles or combinations of vehicles such as mineral oil, vegetableoils, triglycerides, glycols, polyols and surface-active agents.

A compound of the invention may be administered topically (e.g. to thelung, eye or intestines). Thus, embodiments of aspects (a) and (b) abovethat may be mentioned include pharmaceutical formulations andcombination products that are adapted for topical administration. Suchformulations include those in which the excipients (including anyadjuvant, diluent and/or carrier) are topically acceptable.

Topical administration to the lung may be achieved by use of an aerosolformulation. Aerosol formulations typically comprise the activeingredient suspended or dissolved in a suitable aerosol propellant, suchas a chlorofluorocarbon (CFC) or a hydrofluorocarbon (HFC). Suitable CFCpropellants include trichloromonofluoromethane (propellant 11),dichlorotetrafluoromethane (propellant 114), and dichlorodifluoromethane(propellant 12). Suitable HFC propellants include tetrafluoroethane(HFC-134a) and heptafluoropropane (HFC-227). The propellant typicallycomprises 40% to 99.5% e.g. 40% to 90% by weight of the total inhalationcomposition. The formulation may comprise excipients includingco-solvents (e.g. ethanol) and surfactants (e.g. lecithin, sorbitantrioleate and the like). Aerosol formulations are packaged in canistersand a suitable dose is delivered by means of a metering valve (e.g. assupplied by Bespak, Valois or 3M).

Topical administration to the lung may also be achieved by use of anon-pressurised formulation such as an aqueous solution or suspension.This may be administered by means of a nebuliser. Topical administrationto the lung may also be achieved by use of a dry-powder formulation. Adry powder formulation will contain the compound of the disclosure infinely divided form, typically with a mass mean aerodynamic diameter(MMAD) of 1-10 μm. The formulation will typically contain a topicallyacceptable diluent such as lactose, usually of large particle size e.g.an MMAD of 100 μm or more. Examples of dry powder delivery systemsinclude SPINHALER, DISKHALER, TURBOHALER, DISKUS and CLICKHALER.

The compounds of the present invention may also be administeredrectally, for example in the form of suppositories or enemas, whichinclude aqueous or oily solutions as well as suspensions and emulsions.Such compositions are prepared following standard procedures, well knownby those skilled in the art. For example, suppositories can be preparedby mixing the active ingredient with a conventional suppository basesuch as cocoa butter or other glycerides. In this case, the drug ismixed with a suitable non-irritating excipient which is solid atordinary temperatures but liquid at the rectal temperature and willtherefore melt in the rectum to release the drug. Such materials arecocoa butter and polyethylene glycols.

Generally, for compositions intended to be administered topically to theeye in the form of eye drops or eye ointments, the total amount of theinhibitor will be about 0.0001 to less than 4.0% (w/w).

Preferably, for topical ocular administration, the compositionsadministered according to the present invention will be formulated assolutions, suspensions, emulsions and other dosage forms. Aqueoussolutions are generally preferred, based on ease of formulation, as wellas a patient's ability to administer such compositions easily by meansof instilling one to two drops of the solutions in the affected eyes.However, the compositions may also be suspensions, viscous orsemi-viscous gels, or other types of solid or semi-solid compositions.Suspensions may be preferred for compounds that are sparingly soluble inwater.

The compositions administered according to the present invention mayalso include various other ingredients, including, but not limited to,tonicity agents, buffers, surfactants, stabilizing polymer,preservatives, co-solvents and viscosity building agents. Preferredpharmaceutical compositions of the present invention include theinhibitor with a tonicity agent and a buffer. The pharmaceuticalcompositions of the present invention may further optionally include asurfactant and/or a palliative agent and/or a stabilizing polymer.

Various tonicity agents may be employed to adjust the tonicity of thecomposition, preferably to that of natural tears for ophthalmiccompositions. For example, sodium chloride, potassium chloride,magnesium chloride, calcium chloride, simple sugars such as dextrose,fructose, galactose, and/or simply polyols such as the sugar alcoholsmannitol, sorbitol, xylitol, lactitol, isomaltitol, maltitol, andhydrogenated starch hydrolysates may be added to the composition toapproximate physiological tonicity.

Such an amount of tonicity agent will vary, depending on the particularagent to be added. In general, however, the compositions will have atonicity agent in an amount sufficient to cause the final composition tohave an ophthalmically acceptable osmolality (generally about 150-450mOsm, preferably 250-350 mOsm and most preferably at approximately 290mOsm). In general, the tonicity agents of the invention will be presentin the range of 2 to 4% w/w. Preferred tonicity agents of the inventioninclude the simple sugars or the sugar alcohols, such as D-mannitol.

An appropriate buffer system (e.g., sodium phosphate, sodium acetate,sodium citrate, sodium borate or boric acid) may be added to thecompositions to prevent pH drift under storage conditions. Theparticular concentration will vary, depending on the agent employed.Preferably however, the buffer will be chosen to maintain a target pHwithin the range of pH 5 to 8, and more preferably to a target pH of pH5 to 7.

Surfactants may optionally be employed to deliver higher concentrationsof inhibitor. The surfactants function to solubilise the inhibitor andstabilise colloid dispersion, such as micellar solution, microemulsion,emulsion and suspension. Examples of surfactants which may optionally beused include polysorbate, poloxamer, polyosyl 40 stearate, polyoxylcastor oil, tyloxapol, triton, and sorbitan monolaurate. Preferredsurfactants to be employed in the invention have ahydrophile/lipophile/balance “HLB” in the range of 12.4 to 13.2 and areacceptable for ophthalmic use, such as TritonX114 and tyloxapol.

Additional agents that may be added to the ophthalmic compositions ofthe present invention are demulcents which function as a stabilisingpolymer. The stabilizing polymer should be an ionic/charged example withprecedence for topical ocular use, more specifically, a polymer thatcarries negative charge on its surface that can exhibit a zeta-potentialof (−)10-50 mV for physical stability and capable of making a dispersionin water (i.e. water soluble). A preferred stabilising polymer of theinvention would be polyelectrolyte, or polyelectrolytes if more thanone, from the family of cross-linked polyacrylates, such as carbomersand Pemulen®, specifically Carbomer 974p (polyacrylic acid), at 0.1-0.5%w/w.

Other compounds may also be added to the ophthalmic compositions of thepresent invention to increase the viscosity of the carrier. Examples ofviscosity enhancing agents include, but are not limited to:polysaccharides, such as hyaluronic acid and its salts, chondroitinsulfate and its salts, dextrans, various polymers of the cellulosefamily; vinyl polymers; and acrylic acid polymers.

Topical ophthalmic products are typically packaged in multidose form.Preservatives are thus required to prevent microbial contaminationduring use. Suitable preservatives include: benzalkonium chloride,chlorobutanol, benzododecinium bromide, methyl paraben, propyl paraben,phenylethyl alcohol, edentate disodium, sorbic acid, polyquaternium-1,or other agents known to those skilled in the art. Such preservativesare typically employed at a level of from 0.001 to 1.0% w/v. Unit dosecompositions of the present invention will be sterile, but typicallyunpreserved. Such compositions, therefore, generally will not containpreservatives.

The medical practitioner, or other skilled person, will be able todetermine a suitable dosage for the compounds of the invention, andhence the amount of the compound of the invention that should beincluded in any particular pharmaceutical formulation (whether in unitdosage form or otherwise).

Embodiments of the invention that may be mentioned in connection withthe combination products described at (b) above include those in whichthe other therapeutic agent is one or more therapeutic agents that areknown by those skilled in the art to be suitable for treatinginflammatory diseases (e.g. the specific diseases mentioned below).

For example, for the treatment of respiratory disorders (such as COPD orasthma), the other therapeutic agent is one or more agents selected fromthe list comprising:

-   -   steroids (e.g. budesonide, beclomethasone dipropionate,        fluticasone propionate, mometasone furoate, fluticasone        furoate);    -   beta agonists (e.g. terbutaline, salbutamol, salmeterol,        formoterol); and    -   xanthines (e.g. theophylline).

Further, for the treatment of gastrointestinal disorders (such asCrohn's disease or ulcerative colitis), the other therapeutic agent maybe, for example, one or more agents selected from the list comprising:

-   -   5-aminosalicylic acid, or a prodrug thereof (such as        sulfasalazine, olsalazine or bisalazide);    -   corticosteroids (e.g. prednisolone, methylprednisolone, or        budesonide);    -   immunosuppressants (e.g. cyclosporin, tacrolimus, methotrexate,        azathioprine or 6-mercaptopurine);    -   anti-TNFα antibodies (e.g., infliximab, adalimumab, certolizumab        pegol or golimumab);    -   anti-IL12/IL23 antibodies (e.g., ustekinumab) or small molecule        IL12/IL23 inhibitors (e.g., apilimod);    -   Anti-α4β7 antibodies (e.g., vedolizumab);    -   MAdCAM-1 blockers (e.g., PF-00547659);    -   antibodies against the cell adhesion molecule α4-integrin (e.g.,        natalizumab);    -   antibodies against the IL2 receptor a subunit (e.g., daclizumab        or basiliximab);    -   JAK3 inhibitors (e.g., tofacitinib or R348);    -   Syk inhibitors and prodrugs thereof (e.g., fostamatinib and        R-406);    -   Phosphodiesterase-4 inhibitors (e.g., tetomilast);    -   HMPL-004;    -   probiotics;    -   Dersalazine;    -   semapimod/CPSI-2364; and    -   protein kinase C inhibitors (e.g. AEB-071).

For the treatment of eye disorders (such as uveitis), the othertherapeutic agent may be, for example, one or more agents selected fromthe list comprising:

-   -   corticosteroids (e.g. dexamethasone, prednisolone, triamcinolone        acetonide, difluprednate or fluocinolone acetonide);    -   immunosuppressants (e.g. cyclosporin, voclosporin, azathioprine,        methotrexate, mycophenolate mofetil or tacrolimus);    -   anti-TNFα antibodies (e.g., infliximab, adalimumab, certolizumab        pegol, ESBA-105 or golimumab);    -   anti-IL-17A antibodies (e.g., secukinumab);    -   mTOR inhibitors (e.g., sirolimus);    -   VGX-1027;    -   JAK3 inhibitors (e.g., tofacitinib or R348); and    -   protein kinase C inhibitors (e.g. AEB-071).        Medical Uses

The compounds of the invention may be used as monotherapies forinflammatory diseases, or in combination therapies for such diseases.

Thus, embodiments of aspects (e) to (g) above that may be mentionedinclude those in which the compound of formula I, Ia, Ib, Ic, Id or Ie(or pharmaceutically acceptable salt, solvate or isotopic derivativethereof) is the sole pharmacologically active ingredient utilised in thetreatment.

However, in other embodiments of aspects (e) to (g) above, the compoundof formula I, la, Ib, Ic, Id or Ie (or pharmaceutically acceptable salt,solvate or isotopic derivative thereof) is administered to a subject whois also administered one or more other therapeutic agents (e.g. whereinthe one or more other therapeutic agents are as defined above inconnection with combination products).

When used herein, the term “inflammatory disease” specifically includesreferences to any one or more of the following:

-   (i) lung diseases or disorders having an inflammatory component,    such as cystic fibrosis, pulmonary hypertension, lung sarcoidosis,    idiopathic pulmonary fibrosis or, particularly, COPD (including    chronic bronchitis and emphysema), asthma or paediatric asthma;-   (ii) skin diseases or disorders having an inflammatory component,    such as atopic dermatitis, allergic dermatitis, contact dermatitis    or psoriasis;-   (iii) nasal diseases or disorders having an inflammatory component,    such as allergic rhinitis, rhinitis or sinusitis;-   (iv) eye diseases or disorders having an inflammatory component,    such as conjunctivitis, allergic conjunctivitis,    keratoconjunctivitis sicca (dry eye), glaucoma, diabetic    retinopathy, macular oedema (including diabetic macular oedema),    central retinal vein occlusion (CRVO), dry and/or wet age related    macular degeneration (AMD), post-operative cataract inflammation,    or, particularly, uveitis (including posterior, anterior and pan    uveitis), corneal graft and limbal cell transplant rejection; and-   (v) gastrointestinal diseases or disorders having an inflammatory    component, such as gluten sensitive enteropathy (coeliac disease),    eosinophilic esophagitis, intestinal graft versus host disease or,    particularly, Crohn's disease or ulcerative colitis.

References herein to diseases having an inflammatory component includereferences to diseases that involve inflammation, whether or not thereare other (non-inflammatory) symptoms or consequences of the disease.

According to a further aspect of the invention there is provided aprocess for the preparation of a compound of formula I which processcomprises:

(a) reaction of a compound of formula II,

with a compound of formula III,

wherein one of Z¹ and Z² is a structural fragment of formula IV

and the other of Z¹ and Z² is a structural fragment of formula V

where E, L, Ar, X¹, X², R¹ to R⁵, A, A¹, G and G¹ are as hereinbeforedefined, for example under conditions known to those skilled in the art,for example at a temperature from ambient (e.g. 15 to 30° C.) to about110° C. in the presence of a suitable organic solvent (e.g. a polaraprotic solvent such as DMF, THF, 1,4-dioxane, or mixtures thereof);(b) reaction of a compound of formula IIa,

wherein Z¹ is as defined above, with a suitable azide-forming agent(i.e. a suitable source of a leaving group and activated azide ion, suchas diphenyl phosphorazidate; see, for example, Tetrahedron 1974, 30,2151-2157) under conditions known to those skilled in the art, such asat sub-ambient to ambient temperature (e.g. from an initial temperatureof about −5 to 5° C. to ambient temperature post-reaction) in thepresence of an amine base (e.g. triethylamine or a sterically hinderedbase such as N,N-diisopropylethylamine) and a suitable organic solvent(e.g. a polar aprotic solvent such as DMF, THF, 1,4-dioxane, or mixturesthereof), which reaction is followed, without isolation, by thermalrearrangement (e.g. under heating) of the intermediate acyl azide (offormula Z¹—C(O)—N₃) e.g. at ambient temperature (such as from 15 to 30°C.) to provide, in situ, a compound of formula II, which compound isthen reacted with a compound of formula III, as defined above, toprovide the compound of formula I;(c) reaction of a compound of formula IIb,

wherein LG¹ represents a suitable leaving group (e.g. imidazolyl,chloro, or aryloxy) and Z¹ is as defined above, with a compound offormula III, as defined above, for example under conditions known tothose skilled in the art, such as at ambient temperature (e.g. from 15to 30° C.), optionally in the presence of an amine base (e.g. asterically hindered base like N,N-diisopropylethylamine) and a suitableorganic solvent (e.g. an aprotic solvent, such as dichloromethane);(d) reaction of a compound of formula VI,

wherein LG² represents a suitable leaving group (e.g. a halo group suchas chloro or bromo) and E, L, Ar, X¹, X², R¹ to R⁵, A and A¹ are ashereinbefore defined with a compound of formula VII,

wherein G and G¹ are as hereinbefore defined, for example underconditions known to those skilled in the art (e.g. as described in J.Am. Chem. Soc. 2011, 133, 15686-15696), such as at elevated temperature(e.g. from 50 to 110° C.) in the presence of a suitable organic solvent(e.g. a polar aprotic solvent such as DMF, THF, 1,4-dioxane, or mixturesthereof) and, optionally, an acidic catalyst (e.g. a sulfonic acid suchas para-toluenesulfonic acid, for example in the presence ofapproximately 0.5 to 1 equivalents of such an acid relative to thecompound of formula VI or formula VII); or(e) deprotection of an protected derivative of a compound of formula I,under conditions known to those skilled in the art, wherein theprotected derivative bears a protecting group on an O- or N-atom of thecompound of formula I (and, for the avoidance of doubt, a protectedderivative of one compound of formula I may or may not represent anothercompound of formula I).

Compounds of formula II may be prepared according to or by analogy withmethods known to those skilled in the art, for example by reaction of acompound of formula IIa, as defined above, with an azide-forming agent,followed by rearrangement of the intermediate acyl azide (as describedat (b) above; see, for example, Tetrahedron 1974, 30, 2151-2157).

Compounds of formula IIb may be prepared reaction of a compound offormula VIII,

wherein LG¹ is as hereinbefore defined, with a compound of formula IX,

wherein Z¹ is as hereinbefore defined, for example under conditionsknown to those skilled in the art.

Amines of formula IX may be prepared from carboxylic acids of formulaIIa through the route described in (b) above, where the intermediateisocyanate II is hydrolysed with water to give a carbamic acid thatloses carbon dioxide to furnish IX. By the same token, the intermediateisocyanate II can be reacted with an alcohol, such as t-butanol, togenerate a protected version of IX.

Certain carboxylic acids of formula IIa, where Z¹ is a structuralfragment of formula IV, in which both X¹ and X² are nitrogen, may besynthesised employing the route outlined in Scheme 1 below (see also:Bioorg. Med. Chem. Lett. 2007, 17, 354-357). This route commences withcycloaddition of trialkylsilylalkynes X with alkyl (Ak) diazoacetates XIto give pyrazoles XII. These pyrazoles are then coupled with aryl- orheteroaryl-boronic acids XIII, employing copper (II)-mediated Chan-Lamreactions (see, for example: Tetrahedron Lett. 1998, 39, 2941-2944), tofurnish N-arylpyrazole esters XIV. Saponification of esters XIV,typically employing an alkali hydroxide, followed by acidificationfurnishes the desired carboxylic acids.

Certain compounds of formula III in which X¹ and X² both represent N andZ² represents a structural fragment of formula IV, or compounds offormula IX in which X¹ and X² both represent N and Z¹ represents astructural fragment of formula IV, may be synthesised by a route such asthat outlined in Scheme 2. In that route, alkyne ester XV (in whichR^(x) represents, for example, optionally substituted phenyl or,particularly, C₁₋₄ alkyl such as methyl) is reacted with acetonitrile inthe presence of a strong base, such as sodium hydride. The resultingβ-ketonitrile XVI is then condensed with arylhydrazine XVII to yield thedesired 5-aminopyrazole.

On the other hand, certain compounds of formula III in which Z²represents a structural fragment of formula V, or compounds of formulaIX in which Z¹ represents a structural fragment of formula V, may besynthesised employing the route outlined in Scheme 3 (see, for example:WO 2003/072569; and WO 2008/046216), wherein R⁴, R⁵, A, A¹, G and G¹ areas hereinbefore defined, LG¹ and LG² represent leaving groups, e.g.,halogen or methanesulfonyl, and FG represents a real or latent NH₂group, i.e., a group that is readily transformed into an NH₂ group, suchas nitro or a protected variant NH-PG², where PG² is a typicalprotecting group (see, for example: Greene, T. W.; Wuts, P. G. M.Protective Groups in Organic Synthesis; Wiley, 4th revised edition,2006; ISBN-10: 0471697540), e.g., a carbamate ester or carboxamide. Thesequence starts with the base-mediated S_(N)Ar displacement of LG¹ inXIX by the aroxides formed when XVIII is treated with base to generateethers XX. The remaining halogen or methanesulfonyl substituents (LG²)of the ether XX is then displaced i) by an amine of formula VII in asecond S_(N)Ar reaction or (ii) via a Buchwald coupling (see, forexample, WO 2009/017838) with an amine of formula VII to furnish thedesired compound (when FG is NH₂), or XXI (when FG is nitro or NH-PG²).When FG is nitro in XXI, the NH₂ group may be revealed by a reductionreaction, typically done through hydrogenation employing a suitablecatalyst, e.g., palladium on carbon, or employing dissolving metalconditions, such as with iron in glacial acetic acid. Alternatively,when FG is a protecting group, the NH₂ group may be revealed by adeprotection reaction. Although only depicted as taking place in thefinal step of the sequence, it should be noted that the unmasking of thelatent NH₂ group represented by FG can take place at any stage in thesynthetic route shown in Scheme 3.

Certain compounds of formula XIV, where L is a direct bond and E is C₂₋₈alkoxy substituted with NR^(7a)R^(7b), may be synthesised employing theroute highlighted in Scheme 4. In this route, phenols XXIII arealkylated with alkyl halides XXIV, where m is 1-7 and Hal is chloro,bromo or iodo, under basic conditions in Williamson ether syntheses(see, for example: Eur. J. Med. Chem. 2010, 45, 5965-5978). PhenolsXXIII can be prepared from XXII—in which PG¹ is an appropriateprotecting group that masks the reactive phenolic functionality (see,for example: Greene, T. W.; Wuts, P. G. M. Protective Groups in OrganicSynthesis; Wiley, 4th revised edition, 2006; ISBN-10: 0471697540), e.g.,tert-butyldimethylsilyl—by a typical deprotection reaction. Thecompounds of formula XXII may be synthesised using, for example, theabove-mentioned Chan-Lam reactions (Scheme 1) of compounds of formulaXIII where L is a direct bond and E is O-PG¹.

Compounds of formula VI may be synthesised by analogy with the compoundsof formula I (see, for example, alternative processes (a) to (c) above).For example, compounds of formula VI can be prepared by reaction of acompound of formula IIx with a compound of formula IIIIx, wherein thecompounds of formulae IIx and IIIIx take the same definitions as thecompounds of formulae II and Ill, with the exception that one of Z¹ andZ² represents a structural fragment of formula IV, as hereinbeforedefined, and the other of Z¹ and Z² represents a structural fragment offormula Va,

It will be understood by persons skilled in the art that compoundsrepresented by formulae II and IIb are generally reactive intermediates.These intermediates may be formed in situ and reacted directly, withoutisolation, with compounds of formula III to provide compounds of formulaI. Furthermore, it will be understood by those skilled in the art thatthe use of appropriate protective groups may be required during theprocesses described above for any of the groups Z¹ and Z² which possesschemically-sensitive functional groups, for example, a hydroxyl group oran amino function.

Many of the compounds illustrated in the Schemes are either commerciallyavailable, or can be obtained using the cited procedures, or can bereadily prepared by conventional methods by those skilled in the art.See for example Regan, J. et al.; J. Med. Chem. 2003, 46, 4676-4686, WO2000/043384, WO 2007/087448 and WO 2007/089512.

Novel intermediates as described herein form an aspect of the invention.In this respect, further aspects of the invention relate to:

-   (i) a compound of formula II, IIa or IIb as hereinbefore defined,    wherein Z¹ is a structural fragment of formula IV, as hereinbefore    defined, or a salt or protected derivative thereof;-   (ii) a compound of formula III, as hereinbefore defined, wherein Z²    is a structural fragment of formula IV, as hereinbefore defined, or    a salt or protected derivative thereof; and-   (iii) a compound of formula VI, as hereinbefore defined, or a salt    or protected derivative thereof.

In the compounds of formulae II, IIa, IIb, III and VI, the groups E, L,Ar, X¹, X², R¹ to R⁵, A, A¹ and LG², when present, take any of thedefinitions for those groups as hereinbefore defined.

Protected derivatives of the compound of formula IIa include esters(e.g. C₁₋₄ alkyl esters) thereof.

Protected derivatives of the compound of formula III include those inwhich the essential NH₂ group is protected. In this respect, suchprotected derivatives include amides or, particularly, carbamates ofthose compounds. For example, those protected derivatives includecompounds in which a H-atom of the NH₂ group is replaced by:

-   -   R¹—C(O)—, wherein R¹ is H, C₁₋₈ alkyl, phenyl or benzyl, which        latter two groups are optionally substituted by one or more        groups selected from halo, hydroxy, methyl and methoxy; or    -   R″—O—C(O)—, wherein R″ is tert-butyl, phenyl, benzyl or        fluorenyl, which latter three groups are optionally substituted        by one or more groups selected from halo, hydroxy, methyl and        methoxy.

Although alkyne esters of formula XV may be commercially available orprepared by conventional methods, the present applicant has surprisinglydiscovered that the corresponding carboxylic acids of such esters may beadvantageously prepared by a route involving carboxylation of a Grignardreagent containing a trialkylsilyl-protected alkyne.

Thus, according to a further aspect of the invention, there is provideda process for the preparation of a compound of formula XXV,

wherein R^(s1) to R^(s3) independently represent C₁₋₄ alkyl and R² andR³ are as hereinbefore defined, said process comprising the steps of:

-   (i) reaction of a compound of formula XXVI

-   -   wherein R^(s1) to R^(s3), R² and R³ are as hereinbefore defined        and Hal represents a halogen selected from Cl, Br and I, with        carbon dioxide, for example in the presence of a reaction-inert,        aprotic organic solvent (e.g. a fully saturated ether that is        either acyclic, such as diethylether, or is cyclic, such as        THF); and

-   (ii) acidification of the resulting carboxylic acid salt, for    example using an aqueous acid (e.g. an aqueous hydrohalic acid such    as aqueous hydrochloric acid).

In certain embodiments of this aspect of the invention, the compound offormula XXVI is prepared by reaction of the corresponding halo compoundwith magnesium metal. In this embodiment, step (i) of theabove-described process may be replaced by the steps:

-   (ia) reaction of a compound of formula XXVII,

-   -   wherein R^(s1) to R^(s3), Hal, R² and R³ are as hereinbefore        defined, with magnesium metal (e.g. magnesium metal turnings        that have been ground, e.g. by grinding in a pestle and mortar),        for example under an inert atmosphere (e.g. nitrogen or a noble        gas, such as argon) in the presence of a reaction-inert, aprotic        organic solvent (e.g. a fully saturated ether that is either        acyclic, such as diethylether, or is cyclic, such as THF); and

-   (ib) reaction of the resulting compound of formula XXVI with carbon    dioxide, for example in the presence of a reaction-inert, aprotic    organic solvent (e.g. a fully saturated ether that is either    acyclic, such as diethylether, or is cyclic, such as THF).

In particular embodiments, the compound of formula XXVI is formed in thesame solvent system as used for the reaction with carbon dioxide (i.e.the compound of formula XXVII is reacted with carbon dioxide withoutisolation from the reaction mixture in which it is formed).

In any of the above embodiments of this aspect of the invention, any oneor more (e.g. all) of the following may apply.

-   (a) The carbon dioxide is provided in solid form (i.e. as dry ice).-   (b) The compound of formula XXVI is reacted with carbon dioxide by    addition of a solvent mixture containing the compound of formula    XXVI to solid carbon dioxide.-   (c) The solvent mixture containing the compound of formula XXVI    mentioned in (b) above is the solvent mixture in which the compound    of formula XXVI is formed (from the compound of formula XXVII and    magnesium metal).-   (d) The compound of formula XXVII is prepared by a process    comprising the steps of:    -   (i) reaction of a compound of formula XXVIII,

-   -   -   wherein R^(s1) to R^(s3) are as hereinbefore defined, with            an aryl (e.g. phenyl) or C₁₋₆ alkyl lithium reagent (e.g.            t-BuLi or, particularly, n-BuLi), for example under an inert            atmosphere (e.g. nitrogen or a noble gas, such as argon) at            sub-ambient temperature (e.g. from −30 to −80° C.) in the            presence of a reaction-inert, aprotic organic solvent (e.g.            a fully saturated ether that is either acyclic, such as            diethylether, or is cyclic, such as THF), followed by            reaction of the resulting alkynyl lithium intermediate with            a compound of formula XXIX,

-   -   -   wherein R² and R³ are as hereinbefore defined, at            sub-ambient temperature (e.g. from −30 to −80° C., such as            at from about −50° C. to about −70° C.), for example by            addition of the compound of formula XXIX to the reaction            mixture; and

    -   (ii) reaction of the resulting compound of formula XXX,

-   -   -   wherein R^(s1) to R^(s3), R² and R³ are as hereinbefore            defined, with a chlorinating, brominating or iodinating            agent (e.g. a concentrated hydrohalic acid, such as            concentrated hydrochloric acid).

In a further aspect of the invention, there is also provided a processfor the preparation of a compound of formula XXXI,

wherein R² and R³ are as hereinbefore defined, said process comprisingremoval of the —Si(R¹)(R^(s2))(R^(s3)) protecting group from a compoundof formula XXV, as hereinbefore defined, for example under conditionsknown to those skilled in the art (e.g. by contacting the compound offormula XXV at ambient temperature with a mixture of an alkali metalhydroxide (such as KOH) and a C₁₋₄ alkyl alcohol, such as methanol).

In particular embodiments of this aspect of the invention, the compoundof formula XXV is prepared according to a method as described above. Inthis respect, a particular embodiment of the invention relates to aprocess for the preparation of a compound of formula XXXI, ashereinbefore defined, said process comprising:

-   (i) a process as hereinbefore defined for the preparation of a    compound of formula XXV; followed by-   (ii) removal of the —Si(R^(s1))(R^(s2))(R^(s3)) protecting group,    for example under conditions known to those skilled in the art (e.g.    by contacting the compound of formula XXV at ambient temperature    with a mixture of an alkali metal hydroxide (such as KOH) and a C₁₋₄    alkyl alcohol, such as methanol).

In another further aspect of the invention, there is also provided aprocess for the preparation of a compound of formula XV, said processcomprising:

-   (i) a process as hereinbefore defined for the preparation of a    compound of formula XXXI; followed by-   (ii) esterification of the carboxylic acid with a source of the    group R^(X) (e.g. with R^(X)—OH or R^(X)—N₂ or, when R^(X)    represents C₁₋₄ alkyl, with R^(X)—I), for example under conditions    known to those skilled in the art.

Moreover, in a still further aspect of the invention, there is provideda process for the preparation of a compound of formula I, ashereinbefore defined, said process comprising a process as hereinbeforedefined for the preparation of a compound of formula XXV, XXXI or XV.

In the above aspects of the invention relating to the preparation ofcompounds of formulae XXV, XXXI and I, the following may apply:

-   -   R^(s1) to R^(s3) all represent the same C₁₋₄ alkyl group (e.g.        R^(s1) to R^(s3) all represent a C₁₋₂ alkyl group, such as        methyl); and/or    -   R² and R³ both represent C₁₋₃ alkyl (e.g. methyl).

The processes described herein involving the preparation of compounds offormula XXV provide the compound of formula XXXI (a useful intermediatein the synthesis of compounds of formula I) by a route that, compared toknown processes, may possess (for example) one or more of the followingadvantages:

-   -   the use of fewer steps from readily available starting        materials;    -   the use of readily available, cost-effective and/or        environmentally friendly materials;    -   the provision of the product in a high percentage yield;    -   the provision of the product in a form that is easy to isolate        (e.g. from any impurities); and/or    -   the achievement of efficiency with regard to energy and/or        solvents.

A further aspect of the invention relates to a compound of formula XXV,as hereinbefore defined, or a salt or protected derivative thereof.Protected derivatives of the compound of formula XXV include esters(e.g. C₁₋₄ alkyl esters) thereof. Particular compounds of formula XXVthat may be mentioned include those in which R^(s1) to R^(s3), R² and R³take any of the definitions mentioned above for those groups (e.g.R^(s1) to R^(s3), R² and R³ all represent methyl).

The other aspects of the invention described herein (e.g. theabove-mentioned compounds, combinations, methods and uses) may have theadvantage that, in the treatment of the conditions described herein,they may be more convenient for the physician and/or patient than, bemore efficacious than, be less toxic than, have better selectivity over,have a broader range of activity than, be more potent than, producefewer side effects than, have a better pharmacokinetic and/orpharmacodynamic profile than, have more suitable solid state morphologythan, have better stability (e.g. long term stability) than, or may haveother useful pharmacological properties over, similar compounds,combinations, methods (treatments) or uses known in the prior art foruse in the treatment of those conditions or otherwise.

The compounds of the invention may additionally (or alternatively):

-   -   exhibit a long duration of action and/or persistence of action        (e.g. in comparison to other previously disclosed p38 MAP kinase        inhibitors such as, for example, BIRB796);    -   not strongly inhibit GSK 3α (e.g. they may have an IC₅₀ against        GSK 3α of 1500 nM or greater; such as 2,000, 3,000, 4,000,        5,000, 6,000, 7,000, 8,000, 9,000 or 10,000 nM or greater);    -   maintain a relatively high drug concentration between doses        (e.g. a high concentration relative to other previously        disclosed p38 MAP kinase inhibitors such as, for example,        BIRB796);    -   establish and maintain a relatively high drug concentration in a        target tissue following (e.g. topical) administration (e.g. a        high concentration relative to other previously disclosed p38        MAP kinase inhibitors such as, for example, BIRB796);    -   exhibit properties that are particularly suited to topical/local        administration (e.g. following topical/local administration, the        generation of high target tissue concentrations but low plasma        concentrations of the compounds of formula I and/or rapid        clearance of the compounds of formula I from plasma);    -   have a reduced risk of extravascular exposure following        intravenous administration (e.g. due to a low volume of        distribution for the compounds of formula I);    -   exhibit superior potency with respect to selected kinases (e.g.        Syk and/or a panel of kinases, such as Syk, Src and p38 MAPKα);    -   exhibit reduced β -catenin induction and/or inhibition of        mitosis in cells;    -   exhibit no or less time-dependent inhibition of members of the        cytochrome P450 superfamily; and/or    -   produce less problematic (e.g. less toxic) metabolites, e.g.        following administration to a patient.

EXPERIMENTAL METHODS

General Procedures

All starting materials and solvents were obtained either from commercialsources or prepared according to the literature citation. Unlessotherwise stated all reactions were stirred. Organic solutions wereroutinely dried over anhydrous magnesium sulfate. Hydrogenations wereperformed on a Thales H-cube flow reactor under the conditions stated orunder a balloon of hydrogen. Microwave reactions were performed in a CEMDiscover and Smithcreator microwave reactor, heating to a constanttemperature using variable power microwave irradiation.

Normal phase column chromatography was routinely carried out on anautomated flash chromatography system such as CombiFlash Companion orCombiFlash RF system using pre-packed silica (230-400 mesh, 40-63 μm)cartridges. SCX was purchased from Supelco and treated with 1Mhydrochloric acid prior to use. Unless stated otherwise the reactionmixture to be purified was first diluted with MeOH and made acidic witha few drops of AcOH. This solution was loaded directly onto the SCX andwashed with MeOH. The desired material was then eluted by washing with1% NH₃ in MeOH.

Analytical Methods

Analytical HPLC was carried out using an Agilent Zorbax Extend C18,Rapid Resolution HT 1.8 μm column eluting with a gradient of either 0.1%formic acid in MeCN in 0.1% aqueous formic acid or a gradient of MeCN in10 mM Ammonium Bicarbonate; a Waters Xselect CSH C18 3.5 μm eluting witha gradient of 0.1% formic acid in MeCN in 0.1% aqueous formic acid. UVspectra of the eluted peaks were measured using either a diode array orvariable wavelength detector on an Agilent 1100 system.

Analytical LCMS was carried out using an Agilent Zorbax Extend C18,Rapid Resolution HT 1.8 μm column eluting with a gradient of either 0.1%formic acid in MeCN in 0.1% aqueous formic acid or a gradient of MeCN in10 mM Ammonium Bicarbonate; a Waters Xselect CSH C18 3.5 μm eluting witha gradient of 0.1% formic acid in MeCN in 0.1% aqueous formic acid. UVand mass spectra of the eluted peaks were measured using a variablewavelength detector on either an Agilent 1100 with or an AgilentInfinity 1260 LC with 6120 quadrupole mass spectrometer with positiveand negative ion electrospray.

Preparative HPLC was carried out using an Agilent Prep-C18 5 μmPreparative Cartridge using either a gradient of either 0.1% formic acidin MeCN in 0.1% aqueous formic acid or a gradient of MeCN in 10 mMAmmonium Bicarbonate; or a Waters Xselect CSH C18 μm column using agradient 0.1% MeCN in 0.1% aqueous formic acid. Fractions were collectedfollowing detection by UV at 254 nm.

¹H NMR Spectroscopy: ¹H NMR spectra were acquired on a Bruker Avance IIIspectrometer at 400 MHz. Either the central peaks of chloroform-d,dimethylsulfoxide-d₆ or an internal standard of tetramethylsilane wereused as references.

Preparation of 2,2-Dimethylbut-3-ynoic acid (i)2-Methyl-4-(trimethylsilyl)but-3-yn-2-ol

A solution of TMS-acetylene (40 g, 0.407 mol) in THF (200 mL) at −70° C.under N₂ was treated with 2.5 M nBuLi (163 mL, 0.407 mol) such that thetemperature remained below −30° C. On complete addition the mixture wasre-cooled to −70° C. and acetone (23.65 g, 0.407 mol) added dropwisekeeping the temp <−50° C. The reaction mixture was allowed to warm to10° C. and then added to aq. HCl and extracted into Et₂O. The organiclayer was separated and washed with water, dried (MgSO₄) andconcentrated under reduced pressure (water bath <40° C.) to give2-methyl-4-(trimethylsilyl)but-3-yn-2-ol (70 g, quant.) as a pale yellowoil containing residual solvent (no effort was made to remove residualsolvent due to volatility of the product).

(ii) (3-Chloro-3-methylbut-1-yn-1-yl)trimethylsilane

A mixture of 2-methyl-4-(trimethylsilyl)but-3-yn-2-ol (see step (i)above; 63 g, 0.403 mol) in 37% HCl (240 mL) was heated at refluxovernight. After cooling to room temperature the reaction mixture wasadded to ice and the product extracted into pentane. The organicextracts were dried (MgSO₄), filtered through a silica plug, andcautiously concentrated under reduced pressure to give(3-chloro-3-methylbut-1-yn-1-yl)trimethylsilane (58.9 g, 83% over twosteps) as a colourless oil.

(iii) 2,2-Dimethyl-4-(trimethylsilyl)but-3-ynoic acid

Pre-ground (mortar and pestle) magnesium turnings (4.1 g, 0.172 mol)were charged to a 3-neck flask containing THF (75 mL). The mixture wasstirred under N₂ at room temperature whilst ˜3 g of(3-chloro-3-methylbut-1-yn-1-yl)trimethylsilane (see step (ii) above)was added. Once initiation of reaction was observed (exotherm!) theremaining (3-chloro-3-methylbut-1-yn-1-yl)trimethylsilane (12 g;reaction total 15 g, 0.086 mol) was added with cooling so as to keep thetemperature in the range 15-22° C. The reaction mixture was stirred atroom temperature for a further 1 hour before being added to solid CO₂(150 g). After 1 hour, when there was no longer any solid CO₂ present,water was added and the mixture made acidic with HCl. The mixture wasextracted with Et₂O, the organic extracts dried (MgSO₄) and concentratedunder reduced pressure to give2,2-dimethyl-4-(trimethylsilyl)but-3-ynoic acid (15.86 g, 100%) as ayellow oil that solidified on cooling.

(iv) 2,2-Dimethylbut-3-ynoic acid

A mixture of 2,2-dimethyl-4-(trimethylsilyl)but-3-ynoic acid (15.86 g,0.086 mol) and KOH (12.51 g, 0.223 mol) in methanol (150 mL) was stirredfor 1 hour and then concentrated under reduced pressure. The residue wasdiluted with water and acidified with HCl. The mixture was extractedwith Et₂O, the organic extracts dried (MgSO₄) and concentrated underreduced pressure to give 2,2-dimethylbut-3-ynoic acid (9.1 g, 94%) as ayellow oil.

Preparation of Compounds of the Invention

Example 11-(3-(2-Methylbut-3-yn-2-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-(phenylamino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea

(i) 4-((4-Aminonaphthalen-1-yl)oxy)-N-phenylpyrimidin-2-amine

p-TSA monohydrate (2.80 g, 14.72 mmol) was added to a stirred mixture of4-((2-chloropyrimidin-4-yl)oxy)naphthalen-1-amine (see, for example,Cirillo, P. F. et al., WO 2002/92576, 21 Nov. 2000; 8 g, 29.4 mmol) andaniline (6.71 mL, 73.6 mmol) in THF (50 mL) at rt under N₂. The mixturewas heated under reflux for 2 h (reaction mixture solidified), a further50 ml of THF was added and the mixture heated for a further 2 h. Themixture was cooled, diluted with THF (200 mL), the solid filtered andwashed with THF (150 mL). The solid was suspended in DCM (100 mL) and 2MNaOH (35 mL) and the mixture stirred vigorously for 1 h, during whichtime the solid dissolved. The organic layer was separated, the aq. layerextracted with DCM (100 mL) and the organics combined, dried (MgSO₄) andevaporated under reduced pressure. The residue was triturated with etherand filtered to give the sub-title compound (4.18 g).

1H NMR (400 MHz; DMSO-d6) δ 9.46 (s, 1H), 8.32 (d, 1H), 8.18-8.15 (m,1H), 7.64-7.62 (m, 1H), 7.45-7.40 (m, 2H), 7.35 (d, 2H), 7.11 (d, 1H),7.03-6.99 (m, 2H), 6.80 (t, 1H), 6.72 (d, 1H), 6.42 (d, 1H), 5.79 (s,2H).

LCMS m/z 329 (M+H)⁺ (ES⁺)

(ii) 4,4-Dimethyl-3-oxohex-5-ynenitrile

A mixture of methyl 2,2-dimethylbut-3-ynoate (1.10 g, 7.85 mmol) andacetonitrile (0.716 mL, 13.73 mmol) was added dropwise to a stirred,refluxing mixture of NaH, 60% dispersion in mineral oil (0.706 g, 17.66mmol) in THF (65 mL). The mixture was stirred at reflux for 2 hours. Themixture was carefully concentrated under reduced pressure andresuspended in diethyl ether (25 mL). The ether layer was steadilytreated with water (25 mL) and stirred. Once the quench andeffervescence had subsided the organic phase was separated. The aqueouslayer was acidified with 1 M hydrogen chloride (20 mL) and extractedwith diethyl ether (3×25 mL). The combined organic phases were washedwith saturated brine (25 mL) and dried (MgSO₄). The solvent was removedunder reduced pressure to yield the sub-title compound (950 mg).

1H NMR (400 MHz; CDCl₃) δ 3.96 (s, 2H), 2.45 (s, 1H), 1.44 (s, 6H).

(iii) 3-(2-Methylbut-3-yn-2-yl)-1-(p-tolyl)-1H-pyrazol-5-amine

p-Tolylhydrazine, HCl (725 mg, 4.52 mmol) and the product from step (ii)above (979 mg, 5.43 mmol) were heated to reflux in ethanol (15 mL) for 4h. The mixture was concentrated under reduced pressure to yield a brownsolid. Saturated NaHCO3 (15 mL) and water (5 mL) were added and themixture was extracted with diethyl ether (3×15 mL). The combined organicphases were concentrated to dryness on silica gel. The pre-adsorbedsilica was purified by chromatography on the Companion (40 g column,0-20% ethyl acetate:hexanes) to afford the sub-title compound (533 mg)as a dark brown oil which crystallised on standing.

LCMS m/z 240 (M+H)⁺ (ES⁺)

(iv)1-(3-(2-Methylbut-3-yn-2-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-(phenylamino)-pyrimidin-4-yl)oxy)naphthalen-1-yl)urea

The product from step (iii) above (134 mg, 0.560 mmol) and CDI (100 mg,0.616 mmol) were stirred in DCM (1 mL) overnight. The mixture wasconcentrated under reduced pressure before adding a solution of theproduct from step (i) above (184 mg, 0.560 mmol) in THF (2 mL) andstirring at rt for 4 h. The mixture was concentrated under reducedpressure and the residue was triturated in MeCN to yield 180 mg of creamsolid. The solid was purified by chromatography on silica gel (12 gcolumn, 10-50% ethyl acetate/isohexane to afford the product as a creamsolid. The solid was co-evaporated with DCM, triturated in methanol thenrecrystallised in acetonitrile to yield the title compound (96 mg) as awhite solid.

1HNMR (400 MHz; DMSO-d6) δ 9.50 (s, 1H), 9.18 (s, 1H), 8.83 (s, 1H),8.40 (d, 1H), 8.09 (d, 1H), 7.95 (d, 1H), 7.82 (d, 1H), 7.63 (t, 1H),7.56 (t, 1H), 7.49 (d, 2H), 7.41 (d, 3H), 7.34-7.17 (m, 1H), 6.97 (t,2H), 6.78 (t, 1H), 6.58 (d, 1H), 6.55 (s, 1H), 3.11 (s, 1H), 2.42 (s,3H), 1.57 (s, 6H).

LCMS m/z 594 (M+H)⁺ (ES⁺); 592 (M−H)⁻ (ES⁻)

Example 21-(4-((2-((7-Methyl-1H-indazol-5-yl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)-3-(3-(2-methylbut-3-yn-2-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)urea

(i) Phenyl (4-((2-chloropyrimidin-4-yl)oxy)naphthalen-1-yl)carbamate

Phenyl chloroformate (2.65 ml, 21.06 mmol) was added to a stirredmixture of 4-((2-chloropyrimidin-4-yl)oxy)naphthalen-1-amine (see, forexample, Cirillo, P. F. et al., WO 2002/92576, 21 Nov. 2000; 5.45 g,20.06 mmol) and sodium bicarbonate (3.37 g, 40.1 mmol) in DCM (50 ml)and THF (20 ml) at rt. The mixture was stirred for 18 h then a furtherportion of phenyl chloroformate added (0.5 mL) and left for 2 h. Themixture was partitioned between DCM (300 mL) and brine (200 mL), theorganic phase separated, dried (MgSO₄) and evaporated under reducedpressure. The residue was triturated with ether/isohexane to give thesub-title compound (7.38 g) as a light pink solid.

1H NMR (DMSO-d6) 400 MHz, δ: 10.28 (s, 1H), 8.68 (d, 1H), 8.29 (d, 1H),7.84 (d, 1H), 7.76 (d, 1H), 7.72-7.68 (m, 1H), 7.64-7.60 (m, 1H),7.51-7.44 (m, 3H), 7.33-7.26 (m, 4H).

LCMS m/z 392/4 (M+H)⁺ (ES⁺)

(ii)1-(4-((2-Chloropyrimidin-4-yl)oxy)naphthalen-1-yl)-3-(3-(2-methylbut-3-yn-2-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)urea

DMAP (34.4 mg, 0.282 mmol) was added to a solution of3-(2-methylbut-3-yn-2-yl)-1-(p-tolyl)-1H-pyrazol-5-amine (see Example1(iii) above; 337 mg, 1.408 mmol) and the product from step (i) above(579 mg, 1.479 mmol) in anhydrous THF (600 μL) and the reaction heatedat 50° C. for 16 h. After this time the reaction was cooled to ambienttemperature and solvent was removed under reduced pressure to afford abrown oil. The crude product was purified by chromatography on theCompanion (40 g column, 0-5% MeOH in DCM) to afford crude product as adark brown solid. This was repurified by chromatography on silica gel(12 g column, 0-30% ethyl acetate in toluene) to afford the sub-titlecompound (475 mg) as a pale brown solid.

1H NMR (400 MHz; DMSO-d6) δ 9.17 (s, 1H), 8.86 (s, 1H), 8.66 (d, 1H),8.09 (d, 1H), 7.97 (d, 1H), 7.80 (dd, 1H), 7.66 (ddd, 1H), 7.58 (ddd,1H), 7.50-7.45 (m, 2H), 7.45-7.37 (m, 3H), 7.27 (d, 1H), 6.54 (s, 1H),3.09 (s, 1H), 2.41 (s, 3H), 1.56 (s, 6H).

LCMS m/z 537/9 (M+H)⁺ (ES⁺); 535/7 (M−H)⁻ (ES⁻)

(iii)1-(4-((2-((7-Methyl-1H-indazol-5-yl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)-3-(3-(2-methylbut-3-yn-2-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)urea

To a solution of the product from step (ii) above (125 mg, 0.233 mmol)in DMF (2 mL) and THF (1 mL) was added p-TSA (44.3 mg, 0.233 mmol)followed by 7-methyl-1H-indazol-5-amine, HCl (85 mg, 0.466 mmol) and thereaction heated at 60° C. for 22 h. After this time the reaction wascooled to ambient temperature, and partitioned between ethyl acetate (40mL) and sat. aqueous NaHCO₃ (20 mL). The organic phase was washed withwater (20 mL) and saturated brine (20 mL). The organic layer was driedover MgSO₄, filtered and concentrated in vacuo to afford a pale brownsolid. The crude product was dry loaded onto silica and purified bychromatography on silica gel (12 g column, 0-60% EtOAc in toluene) toafford a pale tan powder. The material was further purified bychromatography on silica gel (4 g column (dry loaded), 0-25% (MeOH/1NNH₃) in DCM) to afford the title compound (23 mg) as a pale orangesolid.

1H NMR (400 MHz; DMSO-d6) δ 12.84 (s, 1H), 9.43 (s, 1H), 9.23 (s, 1H),8.91 (s, 1H), 8.38 (d, 1H), 8.15-8.04 (m, 2H), 7.83 (dd, 1H), 7.66-7.48(m, 5H), 7.45-7.29 (m, 4H), 7.02 (br. s, 1H), 6.59-6.54 (m, 2H), 3.09(s, 1H), 2.41 (s, 3H), 2.29 (s, 3H), 1.57 (s, 6H).

LCMS m/z 648 (M+H)⁺ (ES⁺)

Example 31-(3-(2-Methylbut-3-yn-2-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((2-oxoindolin-6-yl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea

To a solution of1-(4-((2-chloropyrimidin-4-yl)oxy)naphthalen-1-yl)-3-(3-(2-methylbut-3-yn-2-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)urea(see Example 2(ii) above; 254 mg, 0.473 mmol) in DMF (4 mL) and THF (2mL) was added p-TSA monohydrate (90 mg, 0.473 mmol) followed by6-aminoindolin-2-one (140 mg, 0.946 mmol) and the reaction heated at 60°C. for 22 h. The reaction mixture was partitioned between ethyl acetate(20 mL) and sat. aqueous sodium bicarbonate (10 mL). The organic layerwas taken, dried over MgSO4, filtered and concentrated under reducedpressure to afford 150 mg of a brown solid. The MgSO4 was washed with10% MeOH/DCM (50 mL) and the washings concentrated under reducedpressure to afford a pale yellow powder which was purified bychromatography on the Companion (12 g column, 0-10% MeOH in DCM) toafford the title compound (50 mg) as a pale yellow powder.

1H NMR (400 MHz; DMSO-d6) δ: 10.19 (s, 1H), 9.49 (s, 1H), 9.16 (s, 1H),8.82 (s, 1H), 8.37 (d, 1H), 8.07 (d, 1H), 7.93 (d, 1H), 7.82 (dd, 1H),7.63 (ddd, 1H), 7.56 (ddd, 1H), 7.50-7.46 (m, 2H), 7.43-7.38 (m, 3H),7.14 (br. s, 1H), 6.95 (br. dd, 1H), 6.79 (br. dd, 1H), 6.56 (s, 1H),6.49 (d, 1H), 3.30 (s, 2H), 3.10 (s, 1H), 2.41 (s, 3H), 6.17 (s, 6H).

LCMS m/z 649 (M+H)⁺ (ES⁺); 647 (M−H)⁻ (ES⁻)

Example 43-Methoxy-5-((4-((4-(3-(3-(2-methylbut-3-yn-2-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)-naphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-N-(2-morpholinoethyl)benzamide

(i) 3-Amino-5-methoxy-N-(2-morpholinoethyl)benzamide

To a stirred mixture of 3-amino-5-methoxybenzoic acid (5.20 g, 31.1mmol), Et₃N (4.50 mL, 32.3 mmol) and 2-morpholinoethanamine (4.23 ml,32.3 mmol) in THF (150 mL) and DMF (4 mL) was added HATU (14.72 g, 38.7mmol) and the reaction stirred at ambient temperature overnight. Afterthis time the mixture was taken up in ethyl acetate (300 mL) and washedwith sat. NaHCO₃ (aq.) (2×100 mL). The aqueous was back extracted withfurther ethyl acetate (4×50 mL) and organics combined, dried over MgSO₄,filtered and concentrated under reduced pressure. Trituration withisohexanes (100 mL) afforded a pale orange gum (15 g). The crude productwas purified by chromatography on the Companion (220 g column, 0-60% IPAin DCM). Fractions were combined as two separate batches to afford thesub-title compound (5.35 g) as an orange solid.

1H NMR (400 MHz; CDCl₃) δ: 6.69-6.64 (m, 3H), 6.35 (t, 1H), 3.81 (br. s,2H), 3.81 (s, 3H), 3.73 (m, 4H), 3.53 (dd, 2H), 2.62-2.57 (m, 2H),2.53-2.49 (m, 4H).

LCMS m/z 280 (M+H)⁺ (ES⁺)

(ii)3-Methoxy-5-((4-((4-(3-(3-(2-methylbut-3-yn-2-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)-naphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-N-(2-morpholinoethyl)benzamide

To a solution of1-(4-((2-chloropyrimidin-4-yl)oxy)naphthalen-1-yl)-3-(3-(2-methylbut-3-yn-2-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)urea(see Example 2(ii) above; 150 mg, 0.251 mmol) and p-TSA monohydrate(47.8 mg, 0.251 mmol) in DMF (2 mL) and THF (1 mL) was added the productfrom step (i) above (146 mg, 0.497 mmol) and the reaction heated at 60°C. for 16 h. After this time further p-TSA monohydrate (100 mg, 0.526mmol) was added and the reaction heated for a further 24 h. The reactionwas then cooled to ambient temperature and partitioned between ethylacetate (50 mL) and sat. aqueous NaHCO₃ (20 mL) and then the organiclayer washed with water (20 mL), brine (20 mL) and then dried overMgSO₄, filtered and evaporated to give a brown oil (257 mg). The crudeproduct was purified by chromatography on the Companion (40 g column,0-5% MeOH/1M NH₃ in DCM) to afford an orange solid which was repurifiedby chromatography on silica gel (25 g column, 0-50% acetone in toluene)then by prep HPLC (Waters, Acidic (0.1% Formic acid), Waters X-SelectPrep-C18, 5 μm, 19×50 mm column, 40-70% MeCN in Water) to afford theproduct as partial formate salts. The product was loaded onto a columnof SCX (2 g) in MeOH (2 mL). The column was washed with MeOH (2 mL) andthen the product was eluted with 0.7 M ammonia in MeOH (10 mL). Theresultant mixture was concentrated in vacuo to afford the title compound(57 mg) as a pale yellow powder.

1H NMR (400 MHz; DMSO-d6) δ 9.59 (s, 1H), 9.13 (s, 1H), 8.84 (s, 1H),8.41 (d, 1H), 8.17 (t, 1H), 8.07 (d, 1H), 7.95 (d, 1H), 7.82 (dd, 1H),7.63 (ddd, 1H), 7.59-7.53 (m 2H), 7.50-7.45 (m, 2H), 7.42-7.37 (m, 3H),7.32 (br. t, 1H), 6.85 (m, 1H), 6.55-6.52 (t, 2H), 3.58-3.53 (7H, m),3.37-3.30 (2H, m), 3.10 (s, 1H), 2.46-2.36 (9H, m), 1.56 (s, 6H).

LCMS m/z 780 (M+H)⁺ (ES⁺); 778 (M−H)⁻ (ES⁻)

Example 51-(3-(2-Methylbut-3-yn-2-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((3-(2-morpholinoethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea

To a solution of1-(4-((2-chloropyrimidin-4-yl)oxy)naphthalen-1-yl)-3-(3-(2-methylbut-3-yn-2-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)urea(see Example 2(ii) above; 100 mg, 0.168 mmol) and p-TSA monohydrate(31.9 mg, 0.168 mmol) in DMF (2 mL) and THF (1 mL) was added3-(2-morpholinoethoxy)aniline (74.5 mg, 0.335 mmol) and the reactionheated at 60° C. for 16 h. After this time further p-TSA monohydrate(63.8 mg, 0.335 mmol) was added and the reaction heated for a further 24h.

The reaction was then cooled to ambient temperature and partitionedbetween ethyl acetate (50 mL) and sat. aqueous NaHCO₃ (20 mL) and thenthe organic layer washed with water (20 mL), brine (20 mL), dried overMgSO₄, filtered and evaporated to give a brown oil. The crude productwas purified by chromatography on the Companion (40 g column, 0-4%MeOH/1M NH₃ in DCM) to an orange solid which was purified bychromatography on silica (25 g column, 0-40% acetone in toluene) toafford a pale yellow solid (102 mg). Trituration with ether (10 mL)afforded an off white solid, 47 mg, the ether washes were shown tocontain product, 50 mg. as a clear oil. Both samples were purified byprep HPLC: (Waters, Acidic (0.1% Formic acid), Waters X-Select Prep-C18,5 μm, 19×50 mm column, 40-70% MeCN in Water) to afford the titlecompound (22 mg) as a pale yellow powder.

1H NMR (400 MHz; DMSO-d6) δ: 9.45 (s, 1H), 9.16 (s, 1H), 8.83 (s, 1H),8.39 (d, 1H), 8.07 (br. d, 1H), 7.96 (d, 1H), 7.82 (dd, 1H), 7.63 (ddd,1H), 7.56 (ddd, 1H), 7.50-7.46 (m, 2H), 7.42-7.38 (m, 3H), 7.12 (br. s,1H), 6.94 (br. d, 1H), 6.87 (br. t, 1H), 6.55 (t, 2H), 6.41 (dd, 1H),3.90 (t, 2H), 3.54 (br. dd, 4H), 3.10 (s, 1H), 2.60 (t, 2H), 2.44-2.39(m, 7H), 1.56 (s, 6H).

LCMS m/z 723 (M+H)⁺ (ES⁺); 721 (M−H)⁻ (ES⁻)

Example 61-(4-((2-((3-(2-(Dimethylamino)ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)-3-(3-(2-methylbut-3-yn-2-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)urea

To a solution of1-(4-((2-chloropyrimidin-4-yl)oxy)naphthalen-1-yl)-3-(3-(2-methylbut-3-yn-2-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)urea(see Example 2(ii) above; 200 mg, 0.335 mmol) and p-TSA monohydrate (191mg, 1.006 mmol) in DMF (2 mL) and THF (3.5 mL) was added3-(2-(dimethylamino)ethoxy)aniline (121 mg, 0.670 mmol) and the reactionheated at 60° C. for 16 h. After this time the reaction was diluted withethyl acetate (20 mL) and washed with sat. aqueous NaHCO₃ (2×10 mL),brine (10 mL), dried over MgSO₄, filtered and concentrated under reducedpressure. The crude product was purified by chromatography on theCompanion (40 g column, 0-10% 1N NH₃/MeOH in DCM) to afford crudeproduct as a pale yellow solid which was purified by preparative HPLC(Waters, Acidic (0.1% Formic acid), Waters X-Select Prep-C18, 5 μm,19×50 mm column, 25-60% MeCN in Water) to afford the desired product asa partial formate salt. The material was loaded in methanol (5 mL) ontoSCX resin (1 g), washed with methanol (5 mL) and then eluted with 0.7 MNH₃ in methanol (10 mL). Solvent was removed under reduced pressure andthe product dried under vacuum at 40° C. to afford the title compound(32 mg) as a pale yellow solid.

1H NMR (400 MHz; DMSO-d6) δ: 9.46 (s, 1H), 9.17 (s, 1H), 8.84 (s, 1H),8.40 (d, 1H), 8.08 (br. dd, 1H), 7.96 (d, 1H), 7.82 (dd, 1H), 7.63 (ddd,1H), 7.57 (ddd, 1H), 7.51-7.46 (m, 2H), 7.43-7.38 (m, 3H), 7.13 (br. s,1H), 6.96 (br. d, 1H), 6.87 (t, 1H), 6.55 (t, 2H), 6.42 (dd, 1H), 3.87(t, 2H), 3.11 (s, 1H), 2.55 (t, 2H), 2.42 (s, 3H), 2.17 (s, 6H), 1.57(s, 6H)

LCMS m/z 681 (M+H)⁺ (ES⁺)

Example 71-(3-(2-Methylbut-3-yn-2-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-(phenylamino)pyridin-4-yl)oxy)naphthalen-1-yl)urea

(i) 4-((4-Aminonaphthalen-1-yl)oxy)-N-phenylpyridin-2-amine

A mixture of 4-((2-chloropyridin-4-yl)oxy)naphthalen-1-amine (see, forexample, Ito, K. et al., WO 2010/112936, 7 Oct. 2010; 600 mg, 2.216mmol), aniline (619 mg, 6.65 mmol) and 4M HCl in dioxane (831 μL, 3.32mmol) in NMP (6 mL) was heated at 140° C. for 18 h. The mixture waspartitioned between EtOAc (150 ml) and aq. NaHCO₃ soln (50 mL), theorganic layer separated, washed with 20% brine (100 mL), dried (MgSO₄)and evaporated under reduced pressure. The crude product was purified bychromatography on silica gel (80 g column, 0-30% EtOAc/isohexane) toafford a solid which was triturated with ether/isohexane, filtered anddried to afford the sub-title compound (328 mg).

1H NMR (400 MHz; CDCl₃) δ 7.97 (d, 1H), 7.87-7.83 (m, 2H), 7.54-7.46 (m,2H), 7.28-7.21 (m, 4H), 7.05-6.99 (m, 2H), 6.90 (s, 1H), 6.74 (d, 1H),6.38 (d, 1H), 6.31-6.29 (m, 1H), 4.11 (brs, 2H).

LCMS m/z 328 (M+H)⁺ (ES⁺)

(ii) Phenyl(4-((2-(phenylamino)pyridin-4-yl)oxy)naphthalen-1-yl)carbamate

Phenyl chloroformate (38 μL, 0.302 mmol) was added to a stirred mixtureof sodium bicarbonate (46.2 mg, 0.550 mmol) and the product from step(i) above (90 mg, 0.275 mmol) in THF (0.6 mL) and DCM (1.5 mL) and thereaction stirred for 2 days at ambient temperature. After this time thereaction was partitioned between DCM (30 mL) and brine (20 mL), theorganic phase separated, dried (MgSO₄) and evaporated under reducedpressure.

LCMS m/z 448 (M+H)⁺ (ES⁺)

(iii)1-(3-(2-Methylbut-3-yn-2-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-(phenylamino)-pyridin-4-yl)oxy)naphthalen-1-yl) urea

A solution of 3-(2-methylbut-3-yn-2-yl)-1-(p-tolyl)-1H-pyrazol-5-amine(see Example 1 (iii) above; 70 mg, 0.293 mmol), DMAP (5 mg, 0.041 mmol)and the product from step (ii) above (125 mg, 0.251 mmol) was heated inanhydrous THF (5 mL) at 50° C. for 22 h. The reaction was cooled,solvent removed under reduced pressure and the crude product dissolvedin DCM (20 mL) and washed with water (10 mL). The DCM layer was isolatedby passing the mixture through a phase separation cartridge and thesolvent evaporated and the crude material purified by preparative HPLC(Waters, Acidic (0.1% Formic acid), Waters X-Select Prep-C18, 5 μm,19×50 mm column, 30-70% MeCN in Water) to afford the title compound(0.3Formic Acid present) (23 mg) as a white powder.

1H NMR (400 MHz; DMSO-d6) δ: 9.22 (s, 1H), 8.89 (d, 2H), 8.25 (s, 0.3H),8.12-8.05 (m, 2H), 7.95 (d, 1H), 7.85 (dd, 1H), 7.65 (ddd, 1H),7.61-7.56 (m, 3H), 7.50-7.45 (m, 2H), 7.42-7.34 (m, 2H), 7.35 (d, 1H),7.22-7.15 (m, 2H), 6.86-6.80 (m, 1H), 6.55-6.51 (m, 2H), 6.08 (d, 1H),3.09 (s, 1H), 2.41 (s, 3H), 1.56 (s, 6H).

LCMS 593 (M+H)⁺ (ES+); 591 (M−H)⁻ (ES⁻)

Example 81-(4-((2-((3-Methoxy-5-(2-morpholinoethoxy)phenyl)amino)pyrimidin-4-yl)oxy)-naphthalen-1-yl)-3-(3-(2-methylbut-3-yn-2-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)urea

(i) 3-Methoxy-5-(2-morpholinoethoxy)aniline

The sub-title compound can be prepared according to or by analogy withprocedures known to those skilled in the art and/or described herein.For example, the following procedure can be used.

To a stirred suspension of 3-amino-5-methoxyphenol (1.400 g, 10.06 mmol)and K₂CO₃ (6.95 g, 50.3 mmol) in pyridine/DMF (18 mL, 1:3) was added4-(2-chloroethyl)morpholine hydrochloride (1.872 g, 10.06 mmol). Theresulting mixture was heated at 60° C. overnight. The reaction wascooled to rt, filtered and concentrated in vacuo to afford a brown oil.The crude product was purified by chromatography on silica gel (40 gcolumn, 0-10% MeOH in DCM) to afford the sub-title compound (1700 mg) asa sticky, orange oil.

1H NMR (DMSO-d6) 400 MHz, δ: 5.75-5.73 (m, 2H) 5.67 (t, 1H) 5.05 (s, 2H)3.94 (t, 2H) 3.61 (s, 3H) 3.58-3.55 (m, 4H) 2.62 (t, 2H) 2.45-2.43 (m,4H).

LCMS m/z 253 (M+H)⁺ (ES+)

(ii)1-(4-((2-((3-Methoxy-5-(2-morpholinoethoxy)phenyl)amino)pyrimidin-4-yl)oxy)-naphthalen-1-yl)-3-(3-(2-methylbut-3-yn-2-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)urea

To a solution of1-(4-((2-chloropyrimidin-4-yl)oxy)naphthalen-1-yl)-3-(3-(2-methylbut-3-yn-2-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)urea(see Example 2(ii) above; 250 mg, 0.419 mmol) and3-methoxy-5-(2-morpholinoethoxy)aniline (see step (i) above; 147 mg,0.583 mmol) in DMF (2 mL) and THF (3.5 mL) was added p-TSA monohydrate(159 mg, 0.838 mmol) and the reaction heated at 60° C. for 24 h.

After this the reaction was diluted with ethyl acetate (20 mL) andwashed with sat. aqueous NaHCO₃ (2×20 mL), brine (10 mL) and the organiclayer dried over MgSO₄, filtered and concentrated under reduced pressureto afford 110 mg crude material as a brown oil. The crude product waspurified by chromatography on silica gel (40 g column, 0-10% ethanol intoluene containing 1% triethylamine) to afford crude product. This wasloaded onto a column of SCX (1 g) in MeOH-DCM 2:1, (1 mL). The columnwas washed with MeOH (10 mL) and DCM (10 mL) and then the product waseluted with 0.7 M ammonia in MeOH. The resultant mixture wasconcentrated in vacuo, triturated with 3:1 ether-isohexanes (10 mL),filtered and then passed through SCX column as before to afford thetitle compound (80 mg) as a pale yellow solid.

1H NMR (400 MHz; DMSO-d6) δ: 9.39 (s, 1H), 9.12 (s, 1H), 8.83 (s, 1H),8.39 (d, 1H), 8.07 (br. d, 1H), 7.97 (d, 1H), 7.82 (dd, 1H), 7.63 (ddd,1H), 7.57 (ddd, 1H), 7.49-7.45 (m, 2H), 7.42-7.37 (m, 3H), 6.78 (br. d,2H), 6.55-6.51 (m, 2H)), 6.03 (t, 1H), 3.88 (t, 2H), 3.57-3.47 (m, 7H),3.09 (s, 1H), 2.59 (t, 2H), 2.43-2.38 (m, 7H), 1.56 (s, 6H).

LCMS 753 (M+H)⁺ (ES⁺); 751 (M−H)⁻ (ES⁻)

Example 91-(2,3-Dichloro-4-((2-((7-methyl-1H-indazol-5-yl)amino)pyrimidin-4-yl)oxy)phenyl)-3-(3-(2-methylbut-3-yn-2-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)urea

(i) 2,3-Dichloro-4-((2-chloropyrimidin-4-yl)oxy)aniline

DBU (11.85 mL, 79 mmol) was added over 5 min to a stirred mixture of4-amino-2,3-dichlorophenol (10 g, 56.2 mmol) in MeCN (150 mL) at 0-5° C.After stirring for 5 min, 2,4-dichloropyrimidine (8.95 g, 60.1 mmol) wasadded portionwise over 5 min then the mixture warmed to rt and stirredfor 2 h. The solvent was evaporated under reduced pressure and theresidue partitioned between ether (200 mL) and water (200 mL). Theaqueous layer was extracted with ether (200 mL) then the combinedorganic layers washed with brine (200 mL), dried (MgSO₄), filteredthrough a pad of silica and evaporated under reduced pressure. Theresidue was triturated with ether-isohexane, filtered and dried toafford the sub-title compound (14.403 g) as a light brown solid.

1H NMR (CDCl₃) 400 MHz, δ: 8.45 (d, 1H), 6.96 (d, 1H), 6.84 (d, 1H),6.73 (d, 1H), 4.22 (s, 2H).

LCMS 290/2/4 (M+H)⁺ (ES⁺)

(ii) Phenyl(3-(2-methylbut-3-yn-2-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)carbamate

To a stirred mixture of3-(2-methylbut-3-yn-2-yl)-1-(p-tolyl)-1H-pyrazol-5-amine (see Example1(iii) above; 526 mg, 2.198 mmol) and sodium bicarbonate (380 mg, 4.52mmol) in anhydrous DCM (6 mL) and anhydrous THF (2 mL) was added phenylchloroformate (305 μL, 2.418 mmol). After 2.5 h a further 0.1 eq ofphenyl chloroformate (30 μL) was added and the reaction stirred afurther hour. After this time the reaction was diluted with DCM (20 mL)and water (20 mL) and passed through a phase separation cartridge.Solvent was removed under reduced pressure to afford the sub-titlecompound (878 mg) as an orange oil.

LCMS 360 (M+H)⁺ (ES⁺); 358 (M−H)⁻ (ES⁻)

(iii)1-(2,3-Dichloro-4-((2-chloropyrimidin-4-yl)oxy)phenyl)-3-(3-(2-methylbut-3-yn-2-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)urea

To the product from step (ii) above (787 mg, 2.19 mmol) and the productof step (i) above (636 mg, 2.190 mmol) in isopropyl acetate (15 mL) wasadded Et₃N (45.8 μL, 0.329 mmol) and the reaction heated at 60° C. over16 h. The reaction was allowed to cool to ambient temperature and awhite precipitate was removed by filtration. Filtrate was concentratedunder reduced pressure and purified by chromatography on silica gel (40g column, 2% Ethanol in toluene) to afford the sub-title compound (200mg) as a pale brown powder (approx 65% purity).

LCMS 555/7 (M+H)⁺ (ES⁺); 553/5 (M−H)⁻ (ES⁻)

(iv)1-(2,3-Dichloro-4-((2-((7-methyl-1H-indazol-5-yl)amino)pyrimidin-4-yl)oxy)phenyl)-3-(3-(2-methylbut-3-yn-2-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)urea

To a solution of the product from step (iii) above (200 mg, 0.234 mmol)and 7-methyl-1H-indazol-5-amine, HCl (86 mg, 0.468 mmol) and DMF (2 mL)was added p-TSA monohydrate (44.5 mg, 0.234 mmol) and the resultingsolution heated at 60° C. for 20 h. After this time the reaction wasdiluted with ethyl acetate (50 mL) and washed with sat. aqueous NaHCO₃(2×20 mL), brine (20 mL), dried over MgSO₄, filtered and concentratedunder reduced pressure to afford a brown solid (210 mg). The crudeproduct was purified by chromatography on the Companion (40 g column,20-50% ethyl acetate in toluene) to afford a yellow powder (44 mg). Thecrude product was purified by preparative HPLC (Waters, Acidic (0.1%Formic acid), Waters X-Select Prep-C18, 5 μm, 19×50 mm column, 35-75%MeCN in Water) to afford the title compound (20 mg) as a white powder.

1H NMR (400 MHz; DMSO-d6) δ: 12.95 (s, 1H), 9.61 (br. s, 1H), 9.41 (s,1H), 9.03 (s, 1H), 8.39 (dd, 1H), 8.25 (br. d, 1H), 7.68 (br. s, 1H),7.60-7.35 (m, 6H), 7.11 (s, 1H), 6.58-6.50 (m, 2H), 3.11 (s, 1H), 2.40(s, 3H), 2.36 (s, 3H), 1.55 (s, 6H).

LCMS 666 (M+H)⁺ (ES⁺); 664 (M−H)⁻ (ES⁻)

Example 101-(4-((2-((6-(2-(Dimethylamino)ethoxy)pyridin-2-yl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)-3-(3-(2-methylbut-3-yn-2-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)urea

(i) 6-(2-(Dimethylamino)ethoxy)pyridin-2-amine

2-(Dimethylamino)ethanol (3.0 ml, 29.8 mmol) was treated with sodium(0.114 g, 4.98 mmol) in a sealed tube and stirred at ambient temperatureuntil homogenous. 6-Chloropyridin-2-amine (1.1 g, 8.30 mmol) was addedand the reaction mixture was heated to 145° C. and stirred in amicrowave tube for 4 h. The reaction was cooled to rt then partitionedbetween EtOAc (50 mL) and water (30 mL). The aqueous phase was extractedwith EtOAc (2×50 mL). The combined organic extracts were washed withbrine (100 mL), dried (MgSO₄), filtered and concentrated in vacuo toafford an oil (1.28 g). The crude product was purified by chromatographyon silica gel (40 g column, 0-10% MeOH/NH₃ in DCM) to afford thesub-title compound (791 mg) as a green oil.

1H NMR (DMSO-d6) 400 MHz, δ: 7.25 (t, 1H) 5.97 (d, 1H) 5.84 (d, 1H) 5.79(br s, 2H) 4.19 (t, 2H) 2.54 (t, 2H) 2.18 (s, 6H).

LCMS 182 (M+H)⁺ (ES⁺)

(ii)4-((4-Aminonaphthalen-1-yl)oxy)-N-(6-(2-(dimethylamino)ethoxy)pyridin-2-yl)pyrimidin-2-amine

A 50 mL flask was charged tert-butyl(4-((2-chloropyrimidin-4-yl)oxy)naphthalen-1-yl)carbamate (see, forexample, Ito, K. et al., WO 2010/067130, 17 Jun. 2010; 965 mg, 2.60mmol), the product from step (i) above (588 mg, 3.24 mmol), Cs₂CO₃ (1269mg, 3.89 mmol), BINAP (404 mg, 0.649 mmol) and Pd₂(dba)₃ (475 mg, 0.519mmol). DMA (22 mL) was added and the mixture purged with nitrogen for 20mins. The reaction was heated at 80° C. overnight. The reaction wascooled to rt. The crude product was loaded directly onto a column ofSCX. The column was washed with MeOH and then the product was elutedwith 1% NH₃ in MeOH. The product-containing fraction was concentrated invacuo to afford crude product as a dark brown semi-solid (1.85 g). Thecrude product was dissolved in DCM (30 mL), TFA (10 mL, 130 mmol) wasadded and the reaction mixture stirred at rt for 3 h. The solvent wasremoved in vacuo and the resulting dark, brown residue dissolved in theminimum quantity of MeOH and loaded onto SCX. The column was eluted withMeOH followed by 1% NH₃ in MeOH. The filtrate was concentrated in vacuoto afford a dark brown oil (1.08 g). The crude product was purified bychromatography on silica gel (80 g column, 0-10% MeOH/NH₃ in DCM) toafford a dark brown oil (507 mg). 53% purity as assessed by 1H NMR. Theproduct was used without further purification.

1H NMR (DMSO-d6) 400 MHz, δ: 9.40 (s, 1H) 8.38 (d, 1H) 8.18-8.13 (m, 1H)7.63-7.59 (m, 1H) 7.44-7.40 (m, 2H) 7.15 (t, 1H) 7.11 (d, 1H) 7.00 (d,1H) 6.71 (d, 1H) 6.50 (d, 1H) 6.24-6.22 (m, 1H) 5.81 (br s, 2H) 4.24 (t,2H) 2.53 (t, 2H) 2.16 (s, 6H).

LCMS 417 (M+H)⁺ (ES⁺)

(iii)1-(4-((2-((6-(2-(Dimethylamino)ethoxy)pyridin-2-yl)amino)pyrimidin-4-yl)oxy)-naphthalen-1-yl)-3-(3-(2-methylbut-3-yn-2-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)urea

To a stirred mixture of phenyl(3-(2-methylbut-3-yn-2-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)carbamate (seeExample 9(ii) above; 271 mg, 0.566 mmol) and the product from step (ii)above (445 mg, 0.566 mmol) in i-PrOAc (6 mL) was added triethylamine(12.23 μl, 0.088 mmol). The resulting mixture was heated at 70° C. for30 mins. The reaction was cooled to rt then partitioned between EtOAc(40 mL) and brine (20 mL). The organic layer was washed with water (20mL), dried (MgSO₄), filtered and concentrated in vacuo to afford a brownsolid (630 mg). The crude product was purified by chromatography onsilica gel (80 g column, 0-10% MeOH/NH₃ in DCM) to afford a foam (468mg). The compound was dissolved in the minimum of MeOH and loaded ontoSCX. The column was eluted with MeOH, the product eluted with 1% NH₃ inMeOH. The filtrate was concentrated in vacuo to afford an orange glass,which was triturated with isohexane/ether. The resulting solid wascollected by filtration and washed with diethyl ether to afford thetitle compound (123 mg) as a beige solid.

1H NMR (DMSO-d6) 400 MHz, δ: 9.44 (s, 1H), 9.18 (s, 1H), 8.82 (s, 1H),8.45 (d, 1H), 8.09 (d, 1H), 7.95 (d, 1H), 7.81 (d, 1H), 7.64-7.60 (m,1H), 7.57-7.53 (m, 1H), 7.50-7.47 (m, 2H), 7.43-7.39 (m, 3H), 7.12 (t,1H), 6.88 (d, 1H), 6.68 (d, 1H), 6.55 (s, 1H), 6.20 (d, 1H), 4.23 (t,2H), 3.10 (s, 1H), 2.53 (t, 2H), 2.41 (s, 3H), 2.16 (s, 6H), 1.56 (s,6H).

LCMS m/z 682 (M+H)⁺ (ES⁺); 680 (M−H)⁻ (ES⁻)

Example 111-(4-((2-((4-(2-(Dimethylamino)ethoxy)pyridin-2-yl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)-3-(3-(2-methylbut-3-yn-2-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)urea

(i) 4-(2-(Dimethylamino)ethoxy)pyridin-2-amine

2-(Dimethylamino)ethanol (3 mL, 29.8 mmol) was treated with sodium (343mg, 14.91 mmol) in a sealed tube and heated at 80° C. until homogenous.4-Chloropyridin-2-amine (1917 mg, 14.91 mmol) was added as a singleportion and the reaction heated in a sealed tube at 145° C. for 1 h. Thereaction was cooled to rt and partitioned between EtOAc (50 mL) andwater (30 mL). The aqueous phase was extracted with EtOAc (2×50 mL). Thecombined organic extracts were washed with brine (100 mL), dried(MgSO₄), filtered and concentrated in vacuo to afford an oil. The crudeproduct was purified by chromatography on silica gel (80 g column, 0-10%MeOH/NH₃ in DCM) to afford the sub-title compound (542 mg) as a whitesolid.

1H NMR (DMSO-d6) 400 MHz, δ: 7.70 (d, 1H) 6.11-6.09 (m, 1H) 5.94 (d, 1H)5.74 (br s, 2H) 3.98 (t, 2H) 2.58 (t, 2H) 2.19 (s, 6H).

LCMS m/z 182 (M+H)⁺ (ES⁺)

(ii)4-((4-Aminonaphthalen-1-yl)oxy)-N-(4-(2-(dimethylamino)ethoxy)pyridin-2-yl)pyrimidin-2-amine

A 50 mL flask was charged tert-butyl(4-((2-chloropyrimidin-4-yl)oxy)naphthalen-1-yl)carbamate (see, forexample, Ito, K. et al., WO 2010/067130, 17 Jun. 2010; 772 mg, 2.077mmol), the product from step (i) above (470 mg, 2.60 mmol), caesiumcarbonate (1015 mg, 3.12 mmol), BINAP (323 mg, 0.519 mmol) and Pd₂(dba)₃(380 mg, 0.415 mmol). DMA (15 mL) was added and the mixture purged withnitrogen for 20 mins. The reaction was heated at 80° C. overnight. Thereaction was cooled to rt. The crude product was loaded directly onto acolumn of SCX in MeOH-DCM. The column was washed with MeOH and then theproduct was eluted with 1% NH₃ in MeOH. The product-containing fractionwas concentrated in vacuo to afford crude product as a dark brown oil(1.66 g). The crude product was dissolved in DCM (25 mL). TFA (8 mL, 104mmol) was added and the reaction mixture stirred at rt for 3 h. Thesolvent was removed in vacuo and the resulting dark, brown residuedissolved in the minimum quantity of MeOH and loaded onto SCX. Thecolumn was eluted with MeOH followed by 1% NH₃ in MeOH. The filtrate wasconcentrated in vacuo to afford a dark brown oil (890 mg). The crudeproduct was purified by chromatography on silica gel (80 g column, 0-10%MeOH/NH₃ in DCM) to afford a dark brown oil (188 mg).

1H NMR (DMSO-d6) 400 MHz, δ: 9.59 (s, 1H) 8.36 (d, 1H) 8.16-8.12 (m, 1H)8.00 (d, 1H) 7.65-7.62 (m, 1H) 7.56 (d, 1H) 7.46-7.40 (m, 2H) 7.14 (d,1H) 6.68 (d, 1H) 6.53 (dd, 1H) 6.33 (d, 1H) 5.81 (s, 2H) 3.84 (t, 2H)2.56 (t, 2H) 2.17 (s, 6H).

LCMS m/z 417 (M+H)⁺ (ES⁺)

(iii)1-(4-((2-((4-(2-(Dimethylamino)ethoxy)pyridin-2-yl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)-3-(3-(2-methylbut-3-yn-2-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)urea

Triethylamine (7.19 μl, 0.052 mmol) was added to a stirred mixturephenyl (3-(2-methylbut-3-yn-2-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)carbamate(see Example 9(ii) above; 159 mg, 0.333 mmol) and the product from step(ii) above (169 mg, 0.333 mmol). The resulting mixture was heated at 70°C. for 30 min. The reaction was cooled to rt then partitioned betweenEtOAc (40 mL) and brine (20 mL). The organic layer was washed with water(20 mL), dried (MgSO₄), filtered and concentrated in vacuo to afford anorange/brown oil (440 mg). The crude product was purified bychromatography on silica gel (40 g column, 0-10% MeOH/NH₃ in DCM)) toafford a solid (287 mg) at ˜86% purity. The solid was triturated withdiethyl ether then MeCN to afford a white solid. The compound wasdissolved in the minimum of MeOH and loaded onto SCX. The column waseluted with MeOH and the product eluted with 1% NH₃ in MeOH. Thefiltrate was concentrated in vacuo to afford an off-white solid, whichwas triturated with diethyl ether. The resulting solid was collected byfiltration and washed with diethyl ether to afford the title compound(52 mg, 0.074 mmol, 22.2% yield) as a white solid.

1H NMR (DMSO-d6) 400 MHz, δ: 10.18 (br s, 1H), 9.42 (s, 1H), 9.14 (s,1H), 8.52-8.51 (m, 1H), 8.21-8.16 (m, 2H), 7.97 (d, 1H), 7.83-7.81 (m,1H), 7.66-7.62 (m, 1H), 7.60-7.56 (m, 1H), 7.51-7.44 (m, 3H), 7.42-7.27(m, 3H), 6.87-6.63 (br m, 2H), 6.51 (s, 1H), 4.33 (br s, 2H), 3.53-3.45(br m, 2H), 3.11 (s, 1H), 2.81 (s, 6H), 2.39 (s, 3H), 1.56 (s, 6H).

LCMS m/z 682 (M+H)⁺ (ES⁺); 680 (M−H)⁻ (ES⁻).

Example 123-((4-((4-(3-(3-(2-Methylbut-3-yn-2-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-N-(2-morpholinoethyl)-5-(trifluoromethyl)benzamide

(i) 3-Amino-N-(2-morpholinoethyl)-5-(trifluoromethyl)benzamide

To a stirred solution of 3-amino-5-(trifluoromethyl)benzoic acid (1.0 g,4.87 mmol), 2-morpholinoethanamine (1.280 mL 9.75 mmol) andtriethylamine (2.038 mL, 14.62 mmol) in DCM (20 mL) was added T3P (50 Wt% in EtOAc, 4.35 mL, 7.31 mmol) carefully, maintaining a temperaturebelow 35° C. The reaction was stirred at rt for 1 h. The mixture waspartitioned with sat. NaHCO₃ soln. (20 mL). The aqueous was separatedand re-partitioned with fresh DCM (20 mL). The combined organics werewashed with 20% w/w NaCl soln. (20 mL), dried (MgSO₄) filtered andconcentrated in vacuo. The crude product was purified by chromatographyon the Companion 40 g column, 2% MeOH:DCM to 5%) to afford the sub-titlecompound (1.43 g) as a yellow oil.

1H NMR (400 MHz; CDCl₃) δ 8.44 (t, 1H), 7.25 (m, 1H), 7.22 (m, 1H), 6.96(s, 1H), 5.78 (s, 2H), 3.57 (t, 4H), 3.36 (q, 2H), 2.40-2.45 (m, 6H).

LCMS m/z 318.0 (M+H)⁺ (ES⁺)

(ii)3-((4-((4-(3-(3-(2-Methylbut-3-yn-2-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-N-(2-morpholinoethyl)-5-(trifluoromethyl)benzamide

A suspension of1-(4-((2-chloropyrimidin-4-yl)oxy)naphthalen-1-yl)-3-(3-(2-methylbut-3-yn-2-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)urea(see Example 2(ii) above; 115 mg, 0.193 mmol), the product from step (i)above (122 mg, 0.384 mmol) and p-TSA monohydrate (73 mg, 0.384 mmol) inTHF/DMF (6 mL, 1:2) was heated at 60° C. for 72 h. The reaction wascooled to rt and partitioned between EtOAc (40 mL) and sat. aq. NaHCO₃(30 mL). The aqueous layer was extracted with EtOAc (2×40 mL). Thecombined organic extracts were washed with water (2×50 mL), brine (2×50mL), dried (MgSO₄), filtered and concentrated in vacuo to afford a foam.The crude product was purified by chromatography on silica gel (40 gcolumn, 0-10% MeOH) to afford a pink solid, which was triturated withdiethyl ether. The material was further purified by prep-HPLC affordingthe title compound (17 mg) as a white solid.

1H NMR (400 MHz; DMSO-d6) δ 9.99 (s, 1H), 9.26 (s, 1H), 8.99 (s, 1H),8.54 (t, 1H), 8.48 (d, 1H), 8.28 (s, 1H), 8.12 (s, 1H), 8.08 (d, 1H),7.94 (d, 1H), 7.82 (d, 1H), 7.55-7.65 (m, 3H), 7.49 (d, 2H), 7.39-7.43(m, 3H), 6.65 (d, 1H), 6.53 (s, 1H), 3.56 (t, 4H), 3.36-3.40 (m, 4H),3.12 (s, 1H), 2.41-2.47 (m, 7H), 1.56 (s, 6H).

LCMS m/z 409 (M+2H)²⁺ (ES⁺)

Example 131-(4-((2-((3-Methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)-3-(3-(2-methylbut-3-yn-2-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)urea

(i) 3-Methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)aniline

1-Bromo-2-(2-(2-methoxyethoxy)ethoxy)ethane (2.75 mL, 15.86 mmol) wasadded to a suspension of 3-amino-5-methoxyphenol (2 g, 14.37 mmol),potassium carbonate (6 g, 43.4 mmol) and sodium iodide (0.215 g, 1.437mmol) in acetone (50 mL) and heated at reflux for 16 h. The mixture waspartitioned between EtOAc (10 mL) and water (10 mL). The organic layerwas separated washed with 20% w/w NaCl soln. (10 mL), dried (MgSO₄),filtered and evaporated. The crude product was purified bychromatography on silica gel (80 g column, 50% EtOAc:isohexane to 100%)to afford the sub-title compound (3.2 g) as a thick brown oil.

1H NMR (400 MHz, DMSO-d6) δ5.76-5.73 (m, 2H), 5.68 (t, 1H), 5.07 (s,2H), 3.98-3.89 (m, 2H), 3.72-3.65 (m, 2H), 3.63 (s, 3H), 3.60-3.48 (m,6H), 3.47-3.40 (m, 2H), 3.24 (s, 3H)

LCMS m/z 286 (M+H)⁺ (ES⁺)

(ii) tert-Butyl(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)carbamate

tert-Butyl (4-((2-chloropyrimidin-4-yl)oxy)naphthalen-1-yl)carbamate(see, for example, Ito, K. et al., WO 2010/067130, 17 Jun. 2010; 1 g,2.69 mmol), the product of step (i) above (1.15 g, 4.03 mmol) and p-TSAmonohydrate (0.100 g, 0.526 mmol) in DMF (10 mL) was heated at 60° C.(block temperature, 55° C. internal temperature) for 14 h. The mixturewas cooled and added dropwise to sat. aq. NaHCO₃ (100 mL) thenpartitioned with EtOAc (2×50 mL). Organics were bulked, washed with 20%w/w NaCl soln. (50 mL), dried (MgSO₄), filtered and solvent evaporated.The crude product was purified by chromatography on silica gel (40 gcolumn) to afford the sub-title compound (1.14 g) as a clear brown oil.

1H NMR (400 MHz, DMSO-d6) δ 9.44 (s, 1H), 9.34 (s, 1H), 8.42 (d, 1H),8.11 (d, 1H), 7.86-7.76 (m, 1H), 7.66-7.49 (m, 3H), 7.39 (d, 1H), 6.85(s, 2H), 6.56 (d, 1H), 6.05 (t, 1H), 3.88 (dd, 2H), 3.71-3.63 (m, 2H),3.59-3.48 (m, 9H), 3.46-3.38 (m, 2H), 3.22 (s, 3H), 1.52 (s, 9H)

LCMS m/z 621 (M+H)⁺ (ES⁺)

(iii)4-((4-Aminonaphthalen-1-yl)oxy)-N-(3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)-ethoxy)phenyl)pyrimidin-2-amine

TFA (2.8 mL, 36.3 mmol) was added dropwise to a stirred solution of theproduct of step (ii) above (1.1 g, 1.772 mmol) in DCM (5 mL). Thereaction was stirred at rt for 2 h. The mixture was added dropwise tostirred water (10 mL) and 1M potassium carbonate solution (35 mL, 35.0mmol) and stirring continued until effervescence ceased. The mixture wasextracted with DCM (2×25 mL) then the combined organic phases were dried(MgSO₄) and concentrated under reduced pressure. The crude product waspurified by chromatography on silica gel (40 g column, 2% MeOH:DCM to5%) to afford a brown gum that was recrystallised from isopropyl acetate(3 mL) afforded the sub-title compound (0.80 g) as a colourless solid.

1H NMR (400 MHz, DMSO-d6) δ 9.42 (s, 1H), 8.33 (d, 1H), 8.22-8.03 (m,1H), 7.69-7.56 (m, 1H), 7.51-7.35 (m, 2H), 7.11 (d, 1H), 6.87 (d, 2H),6.68 (d, 1H), 6.35 (d, 1H), 6.04 (t, 1H), 5.79 (s, 2H), 3.94-3.78 (m,2H), 3.74-3.64 (m, 2H), 3.60-3.47 (m, 9H), 3.46-3.38 (m, 2H), 3.22 (s,3H)

LCMS m/z 521 (M+H)⁺ (ES⁺)

(iv)1-(4-((2-((3-Methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)phenyl)amino)-pyrimidin-4-yl)oxy)naphthalen-1-yl)-3-(3-(2-methylbut-3-yn-2-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)urea

Triethylamine (4 μL, 0.029 mmol) was added to a mixture of phenyl(3-(2-methylbut-3-yn-2-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)carbamate (seeExample 9(ii) above; 50 mg, 0.139 mmol) and the product of step (iii)above (73 mg, 0.140 mmol) in isopropyl acetate (2 mL) and the mixtureheated at 50° C. for 4 h. The crude product was purified bychromatography on silica gel (12 g column, 1% MeOH:DCM to 4%) and theresultant solid triturated with Et₂O (3×2 mL) to afford the titlecompound (48 mg) as a colourless solid.

1H NMR (400 MHz, DMSO-d6) δ 9.43 (s, 1H), 9.13 (s, 1H), 8.85 (s, 1H),8.40 (d, 1H), 8.06 (d, 1H), 7.96 (d, 1H), 7.84-7.79 (m, 1H), 7.69-7.52(m, 2H), 7.51-7.44 (m, 2H), 7.44-7.34 (m, 3H), 6.90-6.69 (m, 2H),6.60-6.47 (m, 2H), 6.03 (t, 1H), 3.91-3.80 (m, 2H), 3.68-3.60 (m, 2H),3.58-3.45 (m, 9H), 3.44-3.37 (m, 2H), 3.21 (s, 3H), 3.11 (s, 1H), 2.41(s, 3H), 1.56 (s, 6H)

LCMS m/z 786 (M+H)⁺ (ES⁺)

Example 143-((4-((4-(3-(3-(2-Methylbut-3-yn-2-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-N-(2-morpholinoethyl)-5-(trifluoromethoxy)benzamide

(i) 3-Amino-5-(trifluoromethoxy)benzoic acid

A mixture of 3-bromo-5-(trifluoromethoxy)benzoic acid (0.5 g, 1.754mmol), sodium azide (0.303 g, 4.66 mmol),N1,N2-dimethylethane-1,2-diamine (0.062 g, 0.702 mmol), copper(I) iodide(0.067 g, 0.351 mmol) and K₃PO₄ (0.819 g, 3.86 mmol) in DMF (5 mL) washeated at 135° C. for 18 h. The mixture was cooled, EtOAc (20 mL) andCelite (2 g) was added then filtered. The filtrate was evaporated underreduced pressure to give a black oil. Repeat in duplicate. The crudeproduct was loaded onto a column of SAX (Discovery® DSC-SAX, apolymer-bound quaternary amine) in MeOH. The column was washed with MeOHand then the product was eluted with 5% AcOH in MeOH. The resultantmixture was concentrated in vacuo then loaded onto a column of SCX inMeOH. The column was washed with MeOH and then the product was elutedwith 0.7 M ammonia in MeOH. The resultant mixture was concentrated invacuo to afford the sub-title compound (450 mg) as a yellow powder.

1H NMR (400 MHz; DMSO-d6) δ 7.15 (s, 1H), 6.87 (s, 1H), 6.57 (s, 1H),5.63 (br s, 2H)

LCMS m/z 222 (M+H)⁺ (ES⁺); 220 (M−H)⁻ (ES⁻)

(ii) 3-Amino-N-(2-morpholinoethyl)-5-(trifluoromethoxy)benzamide

T3P (50% Wt in EtOAc) (1.8 mL, 3.02 mmol) was added over 1 min to asolution of the product of step (i) above (440 mg, 1.990 mmol),2-morpholinoethanamine (520 μL, 3.96 mmol) and TEA (0.83 ml, 5.95 mmol)in DCM (10 mL). The mixture was stirred at rt for 1 h then partitionedwith sat. aq. NaHCO₃ soln. (20 mL) and DCM (30 mL). The organic layerwas separated, washed with brine (20 mL), dried (MgSO₄) and evaporatedunder reduced pressure. The crude product was purified by chromatographyon silica gel (40 g column, 0-5% MeOH/DCM) to afford the sub-titlecompound (520 mg) as a white solid.

1H NMR (400 MHz; CDCl₃) 7.03 (s, 1H), 6.88 (s, 1H), 6.71 (s, 1H), 6.63(s, 1H), 3.98 (s, 2H), 3.74-3.72 (m, 4H), 3.55-3.50 (m, 2H), 2.60 (t,2H), 2.52-2.50 (m, 4H)

LCMS m/z 334 (M+H)⁺ (ES⁺)

(iii)3-((4-((4-(3-(3-(2-Methylbut-3-yn-2-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-N-(2-morpholinoethyl)-5-(trifluoromethoxy)benzamide

A mixture of1-(4-((2-chloropyrimidin-4-yl)oxy)naphthalen-1-yl)-3-(3-(2-methylbut-3-yn-2-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)urea(see Example 2(ii) above; 115 mg, 0.214 mmol), the product of step (ii)above (143 mg, 0.428 mmol) and p-TSA monohydrate (62 mg, 0.326 mmol) inDMF (3 mL) were heated at 60° C. for 18 h. A further portion of p-TSAmonohydrate (62 mg, 0.326 mmol) was added and the mixture heated for afurther 18 h. The mixture was partitioned between EtOAc (50 mL) and aq.sat. NaHCO₃ (50 mL), the organic layer separated, washed with water (40mL), dried (MgSO₄), filtered and evaporated under reduced pressure. Thecrude product was purified by chromatography on silica gel (40 g column,0-5% MeOH/DCM) to afford the title compound (21 mg) as a solid.

1H NMR (400 MHz; DMSO-d6) δ 9.96 (s, 1H), 9.14 (s, 1H), 8.87 (s, 1H),8.48 (d, 1H), 8.41 (t, 1H), 8.08 (d, 1H), 7.99 (d, 1H), 7.96 (s, 1H),7.82 (d, 1H), 7.75 (s, 1H), 7.65-7.40 (m, 7H), 7.23 (s, 1H), 6.66 (d,1H), 6.54 (s, 1H), 3.57-3.54 (m, 4H), 3.12 (s, 1H), 2.45-2.37 (m, 9H),1.57 (s, 6H). (2H under H₂O peak)

LCMS m/z 834 (M+H)⁺ (ES⁺)

Example 153-Ethynyl-5-((4-((4-(3-(3-(2-methylbut-3-yn-2-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-N-(2-morpholinoethyl)benzamide

(i) 3-Amino-5-bromo-N-(2-morpholinoethyl)benzamide

T3P (50 Wt % in EtOAc, 56.2 mL, 94 mmol), was added carefully to asolution of 3-amino-5-bromobenzoic acid (13.6 g, 63.0 mmol),2-morpholinoethanamine (16.52 mL, 126 mmol) and TEA (26.3 mL, 189 mmol)in DCM (200 mL). Ice bath used sporadically to prevent temperaturerising above 35° C. Stirred at rt for 1 h then partitioned with sat. aq.NaHCO₃ soln. (250 mL). Aqueous separated and partitioned with fresh DCM(250 mL), organics separated, bulked and partitioned with 20% w/w NaClsoln. (250 mL). Organic layer was separated, dried (MgSO₄), filtered andsolvent evaporated. The crude product was dissolved in DCM (100 mL) andthe sub-title product (13 g) crystallised out on standing as a light tancrystalline solid.

1H NMR (400 MHz, DMSO-d6) δ 8.29 (t, 1H), 7.06 (t, 1H), 6.98 (t, 1H),6.85 (t, 1H), 5.59 (s, 2H), 3.57 (t, 4H), 3.41-3.26 (m, 2H), 2.48-2.33(m, 6H)

LCMS m/z 328/330 (M+H)⁺ (ES⁺)

(ii)3-Amino-N-(2-morpholinoethyl)-5-((triisopropylsilyl)ethynyl)benzamide

Pd(PPh₃)₄ (2.90 g, 2.51 mmol) was added to a degassed suspension of theproduct of step (i) above (16.5 g, 50.3 mmol), CuI (0.479 g, 2.51 mmol),and ethynyltriisopropyl-silane (16.92 mL, 75 mmol) in TEA (30 mL) andDMF (150 mL). Heated at 85° C. (block temp.) for 5 h, cooled andfiltered (Whatman glass fibre pad GF/C). Solvents evaporated and theresidue partitioned between EtOAc (500 mL) and 20% w/w NaCl soln. (500mL). Aqueous layer was separated and washed with fresh EtOAc (500 mL).Organic layers bulked and washed with fresh 20% w/w NaCl soln. (500 mL),separated, dried (MgSO₄), filtered and solvent evaporated to a thickbrown oil. The crude product was purified by chromatography on silicagel (220 g column, 2% MeOH:DCM to 10%) to afford the sub-title compound(18.5 g) as a pale yellow glass.

1H NMR (400 MHz, DMSO-d6) δ 8.29 (t, 1H), 7.04 (dd, 1H), 7.02 (t, 1H),6.79 (dd, 1H), 5.44 (s, 2H), 3.57 (t, 4H), 3.37-3.28 (m, 2H), 2.47-2.36(m, 6H), 1.11 (s, 21H)

LCMS m/z 430 (M+H)⁺ (ES⁺)

(iii) 3-Amino-5-ethynyl-N-(2-morpholinoethyl)benzamide

The product of step (ii) above (18.5 g, 43.1 mmol) was dissolved inEtOAc (250 mL) and TBAF, 1M in THF (43.1 mL, 43.1 mmol) added. Stirredfor 1 h. Partitioned between water (500 mL) and ethyl acetate (200 mL)organic layer separated and washed with 20% w/w NaCl soln. (400 mL).Organic layer was separated, dried (MgSO₄) filtered and solventsevaporated. The crude product was slurried in Et₂O (100 mL) for 30minutes filtered and washed with fresh Et₂O (20 mL). Oven dried at 45°C. to afford the sub-title compound (9.2 g)

1H NMR (400 MHz, DMSO-d6) δ 8.28 (t, 1H), 7.12-6.97 (m, 2H), 6.76 (t,1H), 5.45 (s, 2H), 4.08 (s, 1H), 3.57 (t, 4H), 3.41-3.25 (m, 2H),2.48-2.32 (m, 6H)

LCMS m/z 274 (M+H)⁺ (ES⁺)

(iv) tert-Butyl(4-((2-((3-ethynyl-5-((2-morpholinoethyl)carbamoyl)phenyl)amino)-pyrimidin-4-yl)oxy)naphthalen-1-yl)carbamate

tert-Butyl (4-((2-chloropyrimidin-4-yl)oxy)naphthalen-1-yl)carbamate(see, for example, Ito, K. et al., WO 2010/067130, 17 Jun. 2010; 6.46 g,17.37 mmol), the product from step (iii) above (7.12 g, 26.0 mmol) andp-TSA monohydrate (5.62 g, 29.5 mmol) in DMF (60 mL) was heated at 60°C. (block temperature, 55° C. internal temperature) for 7 h. The mixturewas cooled and added dropwise to sat. aq. NaHCO₃ (1 L). Solid wasfiltered and washed with water (50 mL) then isohexane (100 mL). Theamorphous solid was stirred in MeOH (200 mL) and product crystallised.Slurried overnight, filtered and solid washed with MeOH (20 mL) anddried to give the sub-title compound (8 g).

1H NMR (400 MHz, DMSO-d6) δ 9.76 (s, 1H), 9.32 (s, 1H), 8.45 (d, 1H),8.41-8.33 (m, 1H), 8.16-8.03 (m, 2H), 7.90 (t, 1H), 7.85-7.78 (m, 1H),7.67-7.51 (m, 3H), 7.48-7.37 (m, 2H), 6.58 (d, 1H), 4.16 (s, 1H), 3.56(t, 4H), 3.46-3.27 (m, 2H), 2.49-2.30 (m, 6H), 1.52 (s, 9H)

LCMS m/z 609 (M+H)⁺ (ES⁺)

(v)3-((4-((4-Aminonaphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-5-ethynyl-N-(2-morpholino-ethyl)benzamide

TFA (22 mL, 286 mmol) was added dropwise to a stirred solution of theproduct of step (iv) above (9 g, 14.05 mmol) in DCM (50 mL). Thereaction was stirred at rt for 2 h. The mixture was added dropwise tostirred water (100 mL) and 1M potassium carbonate solution (280 mL, 280mmol) and stirring continued until effervescence ceased. The mixture wasextracted with DCM (2×250 mL) then the combined organic phases weredried (MgSO₄) and concentrated under reduced pressure. The crude productwas purified by chromatography on the Companion (120 g column, 2%MeOH:DCM to 6%) to afford the sub-title compound (6.7 g) as a pale brownfoam.

1H NMR (400 MHz, DMSO-d6) δ 9.77 (s, 1H), 8.39 (t, 1H), 8.36 (d, 1H),8.17-8.10 (m, 1H), 8.06 (s, 1H), 7.94 (dd, 1H), 7.67-7.59 (m, 1H),7.49-7.38 (m, 3H), 7.15 (d, 1H), 6.70 (d, 1H), 6.37 (d, 1H), 5.79 (s,2H), 4.20 (s, 1H), 3.56 (t, 4H), 3.41-3.30 (m, 2H), 2.48-2.34 (m, 6H)

LCMS m/z 509 (M+H)⁺ (ES⁺)

(vi)3-Ethynyl-5-((4-((4-(3-(3-(2-methylbut-3-yn-2-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)-naphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-N-(2-morpholinoethyl)benzamide

To a stirred solution of phenyl(3-(2-methylbut-3-yn-2-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)-carbamate (seeExample 9(ii) above; 150 mg, 0.409 mmol) and the product of step (v)above (208 mg, 0.409 mmol) in isopropyl acetate (5 mL) was addedtriethylamine (8.84 μL, 0.063 mmol). The resulting solution was heatedat 70° C. for 90 min. The reaction was cooled to rt and the solventremoved in vacuo. The crude product was purified by chromatography onsilica gel (40 g column, 0-10% MeOH in DCM) to afford a semi-solid,which was triturated with a mixture of diethyl ether, acetonitrile andisohexane to afford the title compound (165 mg) as a white solid.

1H NMR (DMSO-d6) 400 MHz, δ: 9.77 (s, 1H), 9.15 (s, 1H), 8.87 (s, 1H),8.84 (d, 1H), 8.41-8.34 (m, 1H), 8.08-8.06 (m, 2H), 7.95 (d, 1H),7.86-7.81 (m, 2H), 7.66-7.62 (m, 1H), 7.59-7.56 (m, 1H), 7.50-7.48 (m,2H), 7.44-7.39 (m, 4H), 6.57 (d, 1H), 6.54 (s, 1H), 4.13 (s, 1H),3.59-3.53 (br m, 4H), 2H under H₂O peak at 3.35 ppm, 3.12 (s, 1H),2.47-2.35 (m, 9H), 1.57 (s, 6H)

LCMS m/z 774 (M+H)⁺ (ES⁺)

Example 161-(3-(2-Methylbut-3-yn-2-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((6-(2-morpholinoethoxy)pyridin-2-yl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea

(i) 6-(2-Morpholinoethoxy)pyridin-2-amine

Sodium hydride (60 Wt % in oil, 2.141 g, 53.5 mmol) was addedportionwise to a stirred solution of 2-morpholinoethanol (6.48 ml, 53.5mmol) stirring in dioxane (70 mL) at 0° C.-5° C. under N₂. This was leftto stir for 30 min before 6-fluoropyridin-2-amine (2 g, 17.84 mmol) wasadded in dioxane (10 mL) over 10 min. After addition, reaction washeated to 90° C. overnight (18 h). The reaction was quenched by the slowaddition of IPA (20 mL) followed by water (50 mL). Dioxane was thenremoved in vacuo and the residue partitioned between EtOAc and water(100 mL each). The organic phase was washed with saturated brine (2×30mL) and then dried over Na₂SO₄, filtered and concentrated in vacuo toafford a light yellow solid. The crude product was purified bychromatography on the Companion (80 g column), using DCM:MeOH:NH₃; 0-5%,to afford the sub-title compound (3.16 g) as a pale yellow solid.

1H NMR (DMSO-d6) 400 MHz, δ: 7.34 (t, 1H), 6.09 (m, 2H), 4.32 (t, 2H),4.32 (br s, 2H), 3.73 (t, 4H), 2.76 (t, 2H), 2.57 (t, 4H)

LCMS m/z 224 (M+H)⁺ (ES⁺)

(ii)4-((4-Aminonaphthalen-1-yl)oxy)-N-(6-(2-morpholinoethoxy)pyridin-2-yl)pyrimidin-2-amine

A mixture of tert-butyl(4-((2-chloropyrimidin-4-yl)oxy)naphthalen-1-yl)carbamate (see, forexample, Ito, K. et al., WO 2010/067130, 17 Jun. 2010; 1.998 g, 5.37mmol), the product of step (i) above (1.5 g, 6.72 mmol), caesiumcarbonate (2.63 g, 8.06 mmol), BINAP (0.837 g, 1.344 mmol) and Pd₂(dba)₃(0.984 g, 1.075 mmol) in DMA (45 mL) was sparged with N₂ for 20 minsbefore heating to 80° C. for 16 h. Reaction was stopped and directlyloaded onto a column of SCX in MeOH. The column was washed with MeOH andthen the product was eluted with 0.7 M ammonia in MeOH. The resultantmixture was concentrated in vacuo to afford a dark brown solid. Theresidue was then taken up in DCM (70 mL) and trifluoroacetic acid (20.70mL, 269 mmol) was added dropwise, reaction was left to stir under N₂ atrt for 2 h. Reaction was stopped and concentrated in vacuo. The darkbrown crude product was loaded onto a column of SCX (15 g) in EtOAc. Thecolumn was washed with EtOAc followed by MeOH and then the product waseluted with 0.7 M ammonia in MeOH. The resultant mixture wasconcentrated in vacuo to afford the product as a dark brown oil. Thecrude product was purified by chromatography on silica gel (80 g column,DCM:MeOH:NH₃; 95:5:0.05) to afford the sub-title compound (1.19 g) as adark brown gum.

LCMS m/z 459 (M+H)⁺ (ES⁺)

(iii)1-(3-(2-Methylbut-3-yn-2-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((6-(2-morpholino-ethoxy)pyridin-2-yl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea

To phenyl(3-(2-methylbut-3-yn-2-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)carbamate (seeExample 9(ii) above; 200 mg, 0.556 mmol) stirring in iso-propyl acetate(3 mL) under N₂ at rt, was added the product of step (ii) above (319 mg,0.556 mmol) in iso-propyl acetate (2 mL) followed by triethylamine (9.27μL, 0.067 mmol) and the reaction mixture heated to 70° C. for 90 min.The reaction was stopped and concentrated in vacuo. The crude productwas purified by chromatography on silica gel (12 g column,EtOAc:Iso-hexane 1:1 to 1:0) to afford a light brown solid. Impure byLCMS therefore re-purified by chromatography on silica gel (40 g column,DCM:MeOH:NH₃ to afford a light red solid which was purified bypreparative HPLC to afford the title compound (20 mg) as a colourlesssolid.

1H NMR (DMSO-d6) 400 MHz; δ 9.44 (s, 1H), 9.20 (s, 1H), 8.84 (s, 1H),8.45 (d, 1H), 8.09 (d, 1H), 8.04 (d, 1H), 7.94 (d, 1H), 7.80 (d, 1H),7.62 (t, 1H), 7.55 (t, 1H), 7.48 (d, 2H), 7.40 (t, 3H), 7.13 (t, 1H),6.89 (d, 1H), 6.54 (s, 1H), 6.21 (d, 1H), 4.27 (t, 2H), 3.52 (t, 4H),3.10 (s, 1H), 2.59 (t, 2H), 2.41 (m, 7H), 1.54 (s, 6H).

LCMS m/z 724 (M+H)⁺ (ES⁺); 722 (M−H)⁻ (ES⁻)

Example 171-(4-((2-((6-(2-(2-(2-Methoxyethoxy)ethoxy)ethoxy)pyridin-2-yl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)-3-(3-(2-methylbut-3-yn-2-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)urea

(i) 6-(2-(2-(2-Methoxyethoxy)ethoxy)ethoxy)pyridin-2-amine

Sodium hydride (60 Wt % in oil, 2.141 g, 53.5 mmol) was addedportionwise to a stirring solution of2-(2-(2-methoxyethoxy)ethoxy)ethanol (8.57 ml, 53.5 mmol) stirring indioxane (70 mL) at 0° C.-5° C. under N₂. This was left to stir for 30min before 6-fluoropyridin-2-amine (2 g, 17.84 mmol) was added indioxane (10 mL) over 10 min. After addition, reaction was heated to 90°C. overnight (18 h). The reaction was quenched by slow addition of IPA(20 mL) followed by water (50 mL). Dioxane was then removed in vacuo andthe residue partitioned between EtOAc and water (100 mL each). Theorganic phase was washed with saturated brine (2×30 mL) and then driedover Na₂SO₄, filtered and concentrated in vacuo to afford the crudeproduct which was purified by chromatography on silica gel (80 g column,DCM:MeOH:NH3, 0-10% MeOH to afford a light brown oil. The product wastaken up in 1M HCl (200 mL) and washed with ether (2×100 mL). Aqueouswas then treated with 2M NaOH to pH 15 and extracted with EtOAc (2×100mL). The organic extracts were combined and washed with saturated brine(1×100 mL) and then dried over Na₂SO₄, filtered and concentrated invacuo affording the sub-title compound (3.52 g).

1H NMR (DMSO-d6) 400 MHz; δ 7.26 (t, 1H), 5.97 (d, 1H), 5.85 (m, 3H),4.72 (t, 2H), 3.67 (t, 2H), 3.51 (m, 6H), 3.42 (t, 2H), 3.23 (s, 3H).

LCMS m/z 258 (M+H)⁺ (ES⁺)

(ii)4-((4-Aminonaphthalen-1-yl)oxy)-N-(6-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)pyridin-2-yl)pyrimidin-2-amine

To a microwave vial was added the product of step (i) above (379 mg,1.479 mmol), tert-butyl(4-((2-chloropyrimidin-4-yl)oxy)naphthalen-1-yl)carbamate (see, forexample, Ito, K. et al., WO 2010/067130, 17 Jun. 2010; 500 mg, 1.345mmol), caesium carbonate (657 mg, 2.017 mmol), palladium(II) acetate(7.55 mg, 0.034 mmol), BINAP (41.9 mg, 0.067 mmol) and dioxane (8 mL).The reaction mixture was purged with N₂ for 10 min and then irradiatedat 100° C. for 15 mins. Reaction was filtered through Celite, the solidswashed with MeOH and the filtrate concentrated in vacuo. The crudeproduct was purified by chromatography on silica gel (40 g column,DCM:MeOH; 1-10% to afford a clear brown oil, 0.80 g. The residue wasthen taken up in DCM (20 mL) and TFA (5180 μL, 67.2 mmol) was addeddropwise and left to stir under N₂ at rt for 1 h. Reaction wasconcentrated in vacuo leaving a brown oil. The crude product was loadedonto a column of SCX (20 g) in MeOH. The column was washed with MeOH andthen the product was eluted with 0.7 M ammonia in MeOH. The resultantmixture was concentrated in vacuo to afford a light brown oil. The crudeproduct required further purification by chromatography on silica gel(40 g column) using DCM:MeOH:NH₃ (1%-5%) to afford the sub-titlecompound (360 mg) as a light brown oil which was used crude in the nextstep.

(iii)1-(4-((2-((6-(2-(2-(2-Methoxyethoxy)ethoxy)ethoxy)pyridin-2-yl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)-3-(3-(2-methylbut-3-yn-2-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)urea

To a stirred mixture of phenyl(3-(2-methylbut-3-yn-2-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)-carbamate (seeExample 9(ii) above; 200 mg, 0.557 mmol) and the product of step (ii)above (360 mg, 0.557 mmol) in i-PrOAc (6 mL) was added triethylamine(12.03 μL, 0.086 mmol). The resulting red solution was heated at 70° C.for 1 hour and 40 minutes. The reaction mixture was allowed to cool toroom temperature and concentrated in vacuo to afford red viscous oil(0.52 g). The crude product was purified by chromatography on silica gel(80 g column, 0-10% MeOH in DMC) then purified further by chromatographyon silica gel (80 g column, iso-hexane:ethyl acetate 1:1). Trituratedwith ether (2×2 mL) and the resultant solid was filtered, rinsing withether, and dried in vacuo to afford the title compound (34 mg) as aclear white crystalline solid.

1H NMR (400 MHz, DMSO-d6) δ 9.45 (s, 1H), 9.19 (s, 1H), 8.83 (s, 1H),8.45 (d, 1H), 8.08 (d, 1H), 7.95 (d, 1H), 7.80 (d, 1H), 7.66-7.59 (m,1H), 7.58-7.52 (m, 1H), 7.49 (d, 2H), 7.41 (t, 3H), 7.14 (t, 1H), 6.89(d, 1H), 6.68 (d, 1H), 6.55 (s, 1H), 6.23 (d, 1H), 4.30-4.21 (m, 2H),3.69-3.62 (m, 2H), 3.54-3.45 (m, 6H), 3.38 (dd, 2H), 3.20 (s, 3H), 3.10(s, 1H), 2.41 (s, 3H), 1.56 (s, 6H)

LCMS m/z 757 (M+H)⁺ (ES⁺); 755 (M−H)⁻ (ES⁻)

Biological Testing: Experimental Methods

Enzyme Inhibition Assays

The enzyme inhibitory activities of compounds disclosed herein aredetermined by FRET using synthetic peptides labelled with both donor andacceptor fluorophores (Z-LYTE, Invitrogen Ltd., Paisley, UK).

p38 MAPKα Enzyme Inhibition

The following two assay variants can be used for determination of p38MAPKα inhibition.

Method 1

The inhibitory activities of test compounds against the p38 MAPKαisoform (MAPK14: Invitrogen), are evaluated indirectly by determiningthe level of activation/phosphorylation of the down-stream molecule,MAPKAP-K2. The p38 MAPKα protein (80 ng/mL, 2.5 μL) is mixed with thetest compound (2.5 μL of either 4 μg/mL, 0.4 μg/mL, 0.04 μg/mL or 0.004μg/mL) for 2 hr at RT. The mix solution (2.5 μL) of the p38a inactivetarget MAPKAP-K2 (Invitrogen, 600 ng/mL) and FRET peptide (8 μM; aphosphorylation target for MAPKAP-K2) is then added and the kinasereaction is initiated by adding ATP (400 μM, 2.5 μL). The mixture isincubated for 1 hr at RT. Development reagent (protease, μL) is addedfor 1 hr prior to detection in a fluorescence microplate reader(Varioskan® Flash, ThermoFisher Scientific).

Method 2

This method follows the same steps as Method 1 above, but utilises ahigher concentration of the p38 MAPKα protein (2.5 μL of 200 ng/mLprotein instead of 2.5 μL of 80 ng/mL protein) for mixing with the testcompound.

p38 MAPKγ Enzyme Inhibition

The inhibitory activities of compounds of the invention against p38MAPKγ(MAPK12: Invitrogen), are evaluated in a similar fashion to thatdescribed hereinabove. The enzyme (800 ng/mL, 2.5 μL) is incubated withthe test compound (2.5 μL at either 4 μg/mL, 0.4 μg/mL, 0.04 μg/mL, or0.004 μg/mL) for 2 hr at RT. The FRET peptides (8 μM, 2.5 μL), andappropriate ATP solution (2.5 μL, 400 μM) is then added to theenzymes/compound mixtures and incubated for 1 hr. Development reagent(protease, 5 μL) is added for 1 hr prior to detection in a fluorescencemicroplate reader (Varioskan® Flash, Thermo Scientific).

c-Src and Syk Enzyme Inhibition

The inhibitory activities of compounds of the invention against c-Srcand Syk enzymes (Invitrogen), are evaluated in a similar fashion to thatdescribed hereinabove. The relevant enzyme (3000 ng/mL or 2000 ng/mLrespectively, 2.5 μL) is incubated with the test compound (either 4μg/mL, 0.4 μg/mL, 0.04 μg/mL, or 0.004 μg/mL, 2.5 μL each) for 2 hr atRT. The FRET peptides (8 μM. 2.5 μL), and appropriate ATP solutions (2.5μL, 800 μM for c-Src, and 60 μM ATP for Syk) are then added to theenzymes/compound mixtures and incubated for 1 hr. Development reagent(protease, 5 μL) is added for 1 hr prior to detection in a fluorescencemicroplate reader (Varioskan® Flash, ThermoFisher Scientific).

GSK 3α Enzyme Inhibition

The following two assay variants can be used for determination of GSK 3αinhibition.

Method 1

The inhibitory activities of compounds of the invention against the GSK3α enzyme isoform (Invitrogen), are evaluated by determining the levelof activation/phosphorylation of the target peptide. The GSK3-α protein(500 ng/mL, 2.5 μL) is mixed with the test compound (2.5 μL at either 4μg/mL, 0.4 μg/mL, 0.04 μg/mL, or 0.004 μg/mL) for 2 hr at RT. The FRETpeptide (8 μM, 2.5 μL), which is a phosphorylation target for GSK3α, andATP (40 μM, 2.5 μL) are then added to the enzyme/compound mixture andthe resulting mixture incubated for 1 hr. Development reagent (protease,5 μL) is added for 1 hr prior to detection in a fluorescence microplatereader (Varioskan® Flash, ThermoFisher Scientific).

In all cases, the site-specific protease cleaves non-phosphorylatedpeptide only and eliminates the FRET signal. Phosphorylation levels ofeach reaction are calculated using the ratio of coumarin emission(donor) over fluorescein emission (acceptor), for which high ratiosindicate high phosphorylation and low ratios indicate lowphosphorylation levels. The percentage inhibition of each reaction iscalculated relative to non-inhibited control and the 50% inhibitoryconcentration (IC₅₀ value) is then calculated from theconcentration-response curve.

Method 2

This method follows the same steps as Method 1 above, but utilises ashorter period of mixing of the test compound (105 minutes instead of 2hours) with the GSK3-α protein.

Cellular Assays

The compounds of the invention were studied using one or more of thefollowing assays.

(a) LPS-Induced TNFα/IL-8 Release in d-U937 Cells

U937 cells, a human monocytic cell line, are differentiated tomacrophage-type cells by incubation with phorbol myristate acetate (PMA;100 ng/mL) for 48 to 72 hr. Cells are pre-incubated with finalconcentrations of test compound for 2 hr and are then stimulated with0.1 μg/mL of LPS (from E. Coli: 0111:B4, Sigma) for 4 hr. Thesupernatant is collected for determination of TNFα and IL-8concentrations by sandwich ELISA (Duo-set, R&D systems). The inhibitionof TNFα production is calculated as a percentage of that achieved by 10μg/mL of BIRB796 at each concentration of test compound by comparisonagainst vehicle control. The relative 50% effective concentration(REC₅₀) is determined from the resultant concentration-response curve.The inhibition of IL-8 production is calculated at each concentration oftest compound by comparison with vehicle control. The 50% inhibitoryconcentration (IC₅₀) is determined from the resultantconcentration-response curve.

(b) LPS-Induced TNFα/IL-8 Release in PBMC Cells

Peripheral blood mononuclear cells (PBMCs) from healthy subjects areseparated from whole blood using a density gradient (Lymphoprep,Axis-Shield Healthcare). The PBMCs are seeded in 96 well plates andtreated with compounds at the desired concentration for 2 hours beforeaddition of 1 ng/mL LPS (Escherichia Coli 0111:B4 from Sigma Aldrich)for 24 hours under normal tissue culture conditions (37° C., 5% CO₂).The supernatant is harvested for determination of IL-8 and TNFαconcentrations by sandwich ELISA (Duo-set, R&D systems) and read on thefluorescence microplate reader (Varioskan® Flash, ThermoFisherScientific). The concentration at 50% inhibition (IC₅₀) of IL-8 and TNFαproduction is calculated from the dose response curve.

(c) IL-2 and IFN Gamma Release in CD3/CD28 Stimulated PBMC Cells

PBMCs from healthy subjects are separated from whole blood using adensity gradient (Lymphoprep, Axis-Shield Healthcare). Cells are addedto a 96 well plate pre-coated with a mixture of CD3/CD38 monoclonalantibodies (0.3 μg/mL eBioscience and 3 μg/mL BD Pharmingenrespectively). Compound at the desired concentration is then added tothe wells and the plate left for 3 days under normal tissue cultureconditions. Supernatants are harvested and IL-2 and IFN gamma releasedetermined by Sandwich ELISA (Duo-set, R&D System). The IC₅₀ isdetermined from the dose response curve.

(d) IL-1-Induced IL-8 Release in HT29 Cells

HT29 cells, a human colon adenocarcinoma cell line, are plated in a 96well plate (24 hrs) and pre-treated with compounds at the desiredconcentration for 2 hours before addition of 5 ng/mL of IL-1β (Abcam)for 24 hours. Supernatants are harvested for IL-8 quantification bySandwich ELISA (Duo-set, R&D System). The IC₅₀ is determined from thedose response curve.

(e) LPS-Induced IL-8 and TNFα Release in Primary Macrophages

PBMCs from healthy subjects are separated from whole blood using adensity gradient (Lymphoprep, Axis-Shield Healthcare). Cells areincubated for 2 hrs and non-adherent cells removed by washing. Todifferentiate the cells to macrophages the cells are incubated with 5ng/mL of GM-CSF (Peprotech) for 7 days under normal tissue cultureconditions. Compounds are then added to the cells at the desiredconcentration for a 2 hour pre-treatment before stimulation with 10ng/mL LPS for 24 hours. Supernatants are harvested and IL-8 and TNFαrelease determined by Sandwich ELISA (Duo-set, R&D System). The IC₅₀ isdetermined from the dose response curve.

(f) Poly I:C-Induced ICAM-1 Expression in BEAS2B Cells

Poly I:C is used in these studies as a simple, RNA virus mimic. PolyI:C-Oligofectamine mixture (1 μg/mL Poly 1:C, ±2% Oligofectamine, 25 μL;Invivogen Ltd., San Diego, Calif., and Invitrogen, Carlsbad, Calif.,respectively) is transfected into BEAS2B cells (human bronchialepithelial cells, ATCC). Cells are pre-incubated with finalconcentrations of test compounds for 2 hr and the level of ICAM1expression on the cell surface is determined by cell-based ELISA. At atime point 18 hr after poly I:C transfection, cells are fixed with 4%formaldehyde in PBS and then endogenous peroxidase is quenched by theaddition of washing buffer (100 μL, 0.05% Tween in PBS: PBS-Tween)containing 0.1% sodium azide and 1% hydrogen peroxide. Cells are washedwith wash-buffer (3×200 μL) and after blocking the wells with 5% milk inPBS-Tween (100 μL) for 1 hr, the cells are incubated with anti-humanICAM-1 antibody (50 μL; Cell Signalling Technology, Danvers, Mass.) in1% BSA PBS overnight at 4° C.

The cells are washed with PBS-Tween (3×200 μL) and incubated with thesecondary antibody (100 μL; HRP-conjugated anti-rabbit IgG, Dako Ltd.,Glostrup, Denmark). The cells are then incubated with of substrate (50μL) for 2-20 min, followed by the addition of stop solution (50 μL, 1NH₂SO₄). The ICAM-1 signal is detected by reading the absorbance at 450nm against a reference wavelength of 655 nm using a spectrophotometer.The cells are then washed with PBS-Tween (3×200 μL) and total cellnumbers in each well are determined by reading absorbance at 595 nmafter Crystal Violet staining (50 μL of a 2% solution in PBS) andelution by 1% SDS solution (100 μL) in distilled water. The measured OD450-655 readings are corrected for cell number by dividing with theOD595 reading in each well. The inhibition of ICAM-1 expression iscalculated at each concentration of test compound by comparison withvehicle control. The 50% inhibitory concentration (IC₅₀) is determinedfrom the resultant concentration-response curve.

(g) Cell Mitosis Assay

Peripheral blood mononucleocytes (PBMCs) from healthy subjects areseparated from whole blood (Quintiles, London, UK) using a densitygradient (Histopaque®-1077, Sigma-Aldrich, Poole, UK). The PBMCs (3million cells per sample) are subsequently treated with 2% PHA(phytohaemagglutinin, Sigma-Aldrich, Poole, UK) for 48 hr, followed by ahr exposure to varying concentrations of test compounds. At 2 hr beforecollection, PBMCs are treated with demecolcine (0.1 μg/mL; Invitrogen,Paisley, UK) to arrest cells in metaphase. To observe mitotic cells,PBMCs are permeabilised and fixed by adding Intraprep (50 μL; BeckmanCoulter, France), and stained with anti-phospho-histone 3 (0.26 ng/L;#9701; Cell Signalling, Danvers, Mass.) and propidium iodide (1 mg/mL;Sigma-Aldrich, Poole, UK) as previously described (Muehlbauer P. A. andSchuler M. J., Mutation Research, 2003, 537:117-130). Fluorescence isobserved using an ATTUNE flow cytometer (Invitrogen, Paisley, UK),gating for lymphocytes. The percentage inhibition of mitosis iscalculated for each treatment relative to vehicle (0.5% DMSO) treatment.

(h) Rhinovirus-Induced IL-8 Release and ICAM-1 Expression

Human rhinovirus RV16 is obtained from the American Type CultureCollection (Manassas, Va.). Viral stocks are generated by infecting Helacells with HRV until 80% of the cells are cytopathic.

BEAS2B cells are infected with HRV at an MOI of 5 and incubated for 2 hrat 33° C. with gentle shaking for to promote absorption. The cells arethen washed with PBS, fresh media added and the cells are incubated fora further 72 hr. The supernatant is collected for assay of IL-8concentrations using a Duoset ELISA development kit (R&D systems,Minneapolis, Minn.).

The level of ICAM1 expressing cell surface is determined by cell-basedELISA. At 72 hr after infection, cells are fixed with 4% formaldehyde inPBS. After quenching endogenous peroxidase by adding 0.1% sodium azideand 1% hydrogen peroxide, wells are washed with wash-buffer (0.05% Tweenin PBS: PBS-Tween). After blocking well with 5% milk in PBS-Tween for 1hr, the cells are incubated with anti-human ICAM-1 antibody in 5% BSAPBS-Tween (1:500) overnight. Wells are washed with PBS-Tween andincubated with the secondary antibody (HRP-conjugated anti-rabbit IgG,Dako Ltd.). The ICAM-1 signal is detected by adding substrate andreading at 450 nm with a reference wavelength of 655 nm using aspectrophotometer. The wells are then washed with PBS-Tween and totalcell numbers in each well are determined by reading absorbance at 595 nmafter Crystal Violet staining and elution by 1% SDS solution. Themeasured OD₄₅₀₋₆₅₅ readings are corrected for cell number by dividingwith the OD₅₉₅ reading in each well. Compounds are added 2 hr before HRVinfection and 2 hr after infection when non-infected HRV is washed out.

(i) Assessment of HRV16 Induced CPE in MRC5

MRC-5 cells are infected with HRV16 at an MOI of 1 in DMEM containing 5%FCS and 1.5 mM MgCl₂, followed by incubation for 1 hr at 33° C. topromote adsorption. The supernatants are aspirated, and then fresh mediaadded followed by incubation for 4 days. Where appropriate, cells arepre-incubated with compound or DMSO for 2 hr, and the compounds and DMSOadded again after washout of the virus.

Supernatants are aspirated and incubated with methylene blue solution(100 μL, 2% formaldehyde, 10% methanol and 0.175% Methylene Blue) for 2hr at RT. After washing, 1% SDS in distilled water (100 μL) is added toeach well, and the plates are shaken lightly for 1-2 hr prior to readingthe absorbance at 660 nm. The percentage inhibition for each well iscalculated. The IC₅₀ value is calculated from the concentration-responsecurve generated by the serial dilutions of the test compounds.

(j) In Vitro RSV Virus Load in Primary Bronchial Epithelial Cells

Normal human bronchial epithelial cells (NHBEC) grown in 96 well platesare infected with RSV A2 (Strain A2, HPA, Salisbury, UK) at an MOI of0.001 in the LHC8 Media:RPMI-1640 (50:50) containing 15 mM magnesiumchloride and incubated for 1 hr at 37° C. for adsorption. The cells arethen washed with PBS (3×200 μL), fresh media (200 μL) is added andincubation continued for 4 days. Where appropriate, cells arepre-incubated with the compound or DMSO for 2 hr, and then added againafter washout of the virus.

The cells are fixed with 4% formaldehyde in PBS solution (50 μL) for 20min, washed with WB (3×200 μL), (washing buffer, PBS including 0.5% BSAand 0.05% Tween-20) and incubated with blocking solution (5% condensedmilk in PBS) for 1 hr. Cells are then washed with WB (3×200 μL) andincubated for 1 hr at RT with anti-RSV (2F7) F-fusion protein antibody(40 μL; mouse monoclonal, lot 798760, Cat. No. ab43812, Abcam) in 5% BSAin PBS-tween. After washing, cells are incubated with an HRP-conjugatedsecondary antibody solution (50 μL) in 5% BSA in PBS-Tween (lot00053170, Cat. No. P0447, Dako) and then TMB substrate added (50 μL;substrate reagent pack, lot 269472, Cat. No. DY999, R&D Systems, Inc.).This reaction is stopped by the addition of 2N H₂SO₄ (50 μL) and theresultant signal is determined colourimetrically (OD: 450 nm with areference wavelength of 655 nm) in a microplate reader (Varioskan®Flash, ThermoFisher Scientific).

Cells are then washed and a 2.5% crystal violet solution (50 μL; lot8656, Cat. No. PL7000, Pro-Lab Diagnostics) is applied for 30 min. Afterwashing with WB, 1% SDS in distilled water (100 μL) is added to eachwell, and plates are shaken lightly on the shaker for 1 hr prior toreading the absorbance at 595 nm. The measured OD₄₅₀₋₆₅₅ readings arecorrected to the cell number by dividing the OD₄₅₀₋₆₅₅ by the OD₅₉₅readings. The percentage inhibition for each well is calculated and theIC₅₀ value is calculated from the concentration-response curve generatedfrom the serial dilutions of compound.

(k) Cell Viability Assay: MTT Assay

Differentiated U937 cells are pre-incubated with each test compound(final concentration 1 μg/mL or 10 μg/mL in 200 μL media indicatedbelow) under two protocols: the first for 4 hr in 5% FCS RPMI1640 mediaand the second in 10% FCS RPMI1640 media for 24 h. The supernatant isreplaced with new media (200 μL) and MTT stock solution (10 μL, 5 mg/mL)is added to each well. After incubation for 1 hr the media are removed,DMSO (200 μL) is added to each well and the plates are shaken lightlyfor 1 hr prior to reading the absorbance at 550 nm. The percentage lossof cell viability is calculated for each well relative to vehicle (0.5%DMSO) treatment. Consequently an apparent increase in cell viability fordrug treatment relative to vehicle is tabulated as a negativepercentage.

(l) Human Biopsy Assay

Intestinal mucosa biopsies are obtained from the inflamed regions of thecolon of IBD patients. The biopsy material is cut into small pieces (2-3mm) and placed on steel grids in an organ culture chamber at 37° C. in a5% CO₂/95% O₂ atmosphere in serum-free media. DMSO control or testcompounds at the desired concentration are added to the tissue andincubated for 24 hr in the organ culture chamber. The supernatant isharvested for determination of IL-6, IL-8, IL-1P and TNFα levels by R&DELISA.

Percentage inhibition of cytokine release by the test compounds iscalculated relative to the cytokine release determined for the DMSOcontrol (100%).

(m) Accumulation of 3 Catenin in d-U937 Cells

U937 cells, a human monocytic cell line, are differentiated intomacrophage-type cells by incubation with PMA; (100 ng/mL) for between 48to 72 hr. The cells are then incubated with either final concentrationsof test compound or vehicle for 18 hr. The induction of p-catenin by thetest compounds is stopped by replacing the media with 4% formaldehydesolution. Endogenous peroxide activity is neutralised by incubating withquenching buffer (100 μL, 0.1% sodium azide, 1% H₂O₂ in PBS with 0.05%Tween-20) for 20 min. The cells are washed with washing buffer (200 μL;PBS containing 0.05% Tween-20) and incubated with blocking solution (200μL; 5% milk in PBS) for 1 hr, re-washed with washing buffer (200 μL) andthen incubated overnight with anti-p-catenin antibody solution (50 μL)in 1% BSA/PBS (BD, Oxford, UK).

After washing with washing buffer (3×200 μL; PBS containing 0.05%Tween-20), cells are incubated with an HRP-conjugated secondary antibodysolution (100 μL) in 1% BSA/PBS (Dako, Cambridge, UK) and the resultantsignal is determined colourimetrically (OD: 450 nm with a referencewavelength of 655 nm) using TMB substrate (50 μL; R&D Systems, Abingdon,UK). This reaction is stopped by addition of 1N H₂SO₄ solution (50 μL).Cells are then washed with washing buffer and 2% crystal violet solution(50 μL) is applied for 30 min. After washing with washing buffer (3×200μL), 1% SDS (100 μL) is added to each well and the plates are shakenlightly for 1 hr prior to measuring the absorbance at 595 nm (Varioskan®Flash, Thermo-Fisher Scientific).

The measured OD₄₅₀₋₆₅₅ readings are corrected for cell number bydividing the OD₄₅₀₋₆₅₅ by the OD₅₉₅ readings. The percentage inductionfor each well is calculated relative to vehicle, and the ratio ofinduction normalised in comparison with the induction produced by astandard control comprising ofN-(4-(4-(3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)pyridin-2-yl)-2-methoxyacetamide(1 μg/mL) which is defined as unity. A signal less than 0.15 of thatobserved for the standard control is designated as “−ve”.

(n) T Cell Proliferation

PBMCs from healthy subjects are separated from whole blood using adensity gradient (Lymphoprep, Axis-Shield Healthcare). The lymphocytefraction is first enriched for CD4+ T cells by negative magnetic cellsorting as per the manufacturer's instructions (Miltenyi Biotec130-091-155). Naïve CD4+ T cells are then separated using positivemagnetic selection of CD45RA+ cells using microbeads as per themanufacturer's instructions (130-045-901). Cells are plated at 2×10⁵cells per well in 100 μL RPMI/10% FBS on 96 well flat bottomed plate(Corning Costar). 25 μL of test compound are diluted to the appropriateconcentration (8× final conc.) in normal medium and added to duplicatewells on the plate to achieve a dose response range of 0.03 ng/mL-250ng/mL. DMSO is added as a negative control. Plates are allowed topre-incubate for 2 hours before stimulation with 1 μg/mL anti-CD3 (OKT3;eBioscience). After 72 h, the medium in each well is replaced with 150μL of fresh medium containing 10 μM BrdU (Roche). After 16 h, thesupernatant is removed, the plate is dried and the cells fixed by adding100 μL of fix/denature solution to each well for 20 min as per themanufacturer's instructions (Roche). Plates are washed once with PBSbefore addition of the anti-BrdU detection antibody and incubated for 90mins at room temperature. Plates are then washed gently 3× with the washbuffer supplied and developed by addition of 100 μL of substratesolution. The reaction is stopped by addition of 50 μL of 1 M H₂SO₄, andread for absorbance at 450 nm on a plate reader (Varioskan® Flash,ThermoFisher Scientific). The IC₅₀ is determined from the dose responsecurve.

(o) IL-2 and IFNγ Release in CD3/CD28 Stimulated LPMC Cells from IBDPatients

Lamina propria mononuclear cells (LPMCs) are isolated and purified frominflamed IBD mucosa of surgical specimens or from normal mucosa ofsurgical specimens as follows: The mucosa is removed from the deeperlayers of the surgical specimens with a scalpel and cut in fragments 3-4mm size. The epithelium is removed by washing the tissue fragments threetimes with 1 mM EDTA (Sigma-Aldrich, Poole, UK) in HBSS (Sigma-Aldrich)with agitation using a magnetic stirrer, discarding the supernatantafter each wash. The sample is subsequently treated with type 1Acollagenase (1 mg/mL; Sigma-Aldrich) for 1 h with stirring at 37° C. Theresulting cell suspension is then filtered using a 100 μm cell strainer,washed twice, resuspended in RPMI-1640 medium (Sigma-Aldrich) containing10% fetal calf serum, 100 U/mL penicillin and 100 μg/mL streptomycin,and used for cell culture.

Freshly isolated LPMCs (2×10⁵ cells/well) are stimulated with 1 μg/mLα-CD3/α-CD28 for 48 h in the presence of either DMSO control orappropriate concentrations of compound. After 48 h, the supernatant isremoved and assayed for the presence of TNFα and IFNγ by R&D ELISA.Percentage inhibition of cytokine release by the test compounds iscalculated relative to the cytokine release determined for the DMSOcontrol (100%).

(p) Inhibition of Cytokine Release from Myofibroblasts Isolated from IBDPatients

Myofibroblasts from inflamed IBD mucosa are isolated as follows:

The mucosa is dissected and discarded and 1 mm-sized mucosal samples arecultured at 37° C. in a humidified CO₂ incubator in Dulbecco's modifiedEagle's medium (DMEM, Sigma-Aldrich) supplemented with 20% FBS, 1%non-essential amino acids (Invitrogen, Paisley, UK), 100 U/mLpenicillin, 100 μg/mL streptomycin, 50 μg/mL gentamycin, and 1 μg/mLamphotericin (Sigma-Aldrich). Established colonies of myofibroblasts areseeded into 25-cm² culture flasks and cultured in DMEM supplemented with20% FBS and antibiotics to at least passage 4 to provide a sufficientquantity for use in stimulation experiments.

Subconfluent monolayers of myofibroblasts are then seeded in 12-wellplates at 3×10⁵ cells per well are starved in serum-free medium for 24 hat 37° C., 5% CO₂ before being cultured for 24 h in the presence ofeither DMSO control or appropriate concentrations of compound. After 24h the supernatant is removed and assayed for the presence of IL-8 andIL-6 by R&D ELISA. Percentage inhibition of cytokine release by the testcompounds is calculated relative to the cytokine release determined forthe DMSO control (100%).

(q) Human Neutrophil Dearanulation

Neutrophils are isolated from human peripheral blood as follows:

Blood is collected by venepuncture and anti-coagulated by addition of1:1 EDTA: sterile phosphate buffered saline (PBS, no Ca+/Mg+). Dextran(3% w/v) is added (1 part dextran solution to 4 parts blood) and theblood allowed to stand for approximately 20 minutes at rt. Thesupernatant is carefully layered on a density gradient (Lymphoprep,Axis-Shield Healthcare) and centrifuged (15 mins, 2000 rpm, no brake).The supernatant is aspirated off and the cell pellet is re-suspended insterile saline (0.2%) for no longer than 60 seconds (to lysecontaminating red blood cells). 10 times volume of PBS is then added andthe cells centrifuged (5 mins, 1200 rpm). Cells are re-suspended inHBSS+ (Hanks buffered salt solution (without phenol red) containingcytochalasin B (5 μg/mL) and 1 mM CaCl₂) to achieve 5×10⁶ cells/mL.

5×10⁴ cells are added to each well of a V-bottom 96 well plate andincubated (30 mins, 37° C.) with the appropriate concentration of testcompound (0.3-1000 ng/mL) or vehicle (DMSO, 0.5% final conc).Degranulation is stimulated by addition of fMLP (final conc 1 μM) whichafter a further incubation (30 mins, 37° C.) the cells are removed bycentrifugation (5 mins, 1500 rpm) and the supernatants transferred to aflat bottom 96 well plate. An equal volume of tetramethylbenzidine (TMB)is added and after 10 mins the reaction terminated by addition of anequal volume of sulphuric acid (0.5 M) and absorbance read at 450 nm(background at 655 nm subtracted). The 50% inhibitory concentration(IC₅₀) is determined from the resultant concentration-response curve.

(r) Cell Cytotoxicity Assay

5×10⁴ TK6 cells (lymphoblastic T cell line) are added to the appropriatenumber of wells of a 96 well plate in 195 μL of media (RPMI supplementedwith 10% foetal bovine serum). 5 μL of DMSO control (final concentration0.5% v/v) or test compound (final concentration either 5 or 1 μg/mL) isadded to the wells and incubated at 37° C., 5% CO₂. After 24 hours, theplate is centrifuged at 1300 rpm for 3 minutes and the supernatantdiscarded. Cells are then resuspended in 7.5 μg/mL propidium iodide (PI)in PBS. After 15 minutes, cells are analysed by flow cytometry (BDaccuri). The % viability is calculated as the % of cells that are PInegative in the test wells normalised to the DMSO control.

In Vivo Screening: Pharmacodynamics and Anti-Inflammatory Activity

(i) LPS-Induced Neutrophil Accumulation in Mice

Non-fasted Balb/c mice are dosed by the intra tracheal route with eithervehicle, or the test substance at the indicated times (within the range2-8 hr) before stimulation of the inflammatory response by applicationof an LPS challenge. At T=0, mice are placed into an exposure chamberand exposed to LPS (7.0 mL, 0.5 mg/mL solution in PBS) for 30 min. Aftera further 8 hr the animals are anesthetized, their tracheas cannulatedand BALF extracted by infusing and then withdrawing from their lungs 1.0mL of PBS via the tracheal catheter. Total and differential white cellcounts in the BALF samples are measured using a Neubaur haemocytometer.Cytospin smears of the BALF samples are prepared by centrifugation at200 rpm for 5 min at RT and stained using a DiffQuik stain system (DadeBehring). Cells are counted using oil immersion microscopy. Data forneutrophil numbers in BAL are shown as mean±S.E.M. (standard error ofthe mean). The percentage inhibition of neutrophil accumulation iscalculated for each treatment relative to vehicle treatment.

(ii) Cigarette Smoke Model

A/J mice (males, 5 weeks old) are exposed to cigarette smoke (4%cigarette smoke, diluted with air) for 30 min/day for 11 days using aTobacco Smoke Inhalation Experiment System for small animals (ModelSIS-CS; Sibata Scientific Technology, Tokyo, Japan). Test substances areadministered intra-nasally (35 μL of solution in 50% DMSO/PBS) oncedaily for 3 days after the final cigarette smoke exposure. At 12 hrafter the last dosing, each of the animals is anesthetized, the tracheacannulated and bronchoalveolar lavage fluid (BALF) is collected. Thenumbers of alveolar macrophages and neutrophils are determined by FACSanalysis (EPICS® ALTRA II, Beckman Coulter, Inc., Fullerton, Calif.,USA) using anti-mouse MOMA2 antibody (macrophage) or anti-mouse 7/4antibody (neutrophil).

(iii) DSS-Induced Colitis in Mice

Non-fasted, 10-12 week old, male BDF1 mice are dosed by oral gavagetwice daily with either vehicle, reference item (5-ASA) or test compoundone day before (Day −1) stimulation of the inflammatory response bytreatment with dextran sodium sulphate (DSS). On Day 0 of the study DSS(5% w/v) is administered in the drinking water followed by BID dosing ofthe vehicle (5 mL/kg), reference (100 mg/kg) or test compound (5 mg/kg)for 7 days. The drinking water with DSS is replenished every 3 days.During the study animals are weighed every day and stool observationsare made and recorded as a score, based on stool consistency. At thetime of sacrifice on Day+6 the large intestine is removed and the lengthand weight are recorded. Sections of the colon are taken for either MPOanalysis to determine neutrophil infiltration or for histopathologyscoring to determine disease severity.

(iv) TNBS-Induced Colitis in Mice

Non-fasted, 10-12 week old, male BDF1 mice are dosed by oral gavagetwice daily with either vehicle (5 mL/kg), reference item (Budesonide2.5 mg/kg) or test compound (1 or 5 mg/kg) one day before (Day −1)stimulation of the inflammatory response by treatment with2,4,6-trinitrobenzenesulphonic acid (TNBS) (15 mg/mL in 50% ethanol/50%saline). On Day 0 of the study TNBS (200 μL) is administeredintra-colonically via a plastic catheter followed by BID dosing of thevehicle, reference or test compound for 2 or 4 days. During the studyanimals are weighed every day and stool observations are made andrecorded as a score, based on stool consistency. At the time ofsacrifice on Day 2 (or Day 4) the large intestine is removed and thelength and weight recorded. Sections of the colon are taken for eitherMPO analysis to determine neutrophil infiltration or for histopathologyinvolving scoring to determine disease severity.

(v) Adoptive Transfer in Mice

On Study day 0, female Balb/C mice are terminated and spleens obtainedfor CD45RB^(high) cell isolation (Using SCID IBD cell Separationprotocol). Approximately 4×10⁵ cells/mL CD45RB^(high) cells are theninjected IP (100 μL/mouse) into female SCID animals. On study day 14,mice are weighed and randomized into treatment groups based on bodyweight. On Day 21 compounds are administered BID, via oral gavage, in apeanut oil vehicle at the dose levels outlined below and a dose volumeof 5 mL/kg. Treatment continues until study day 42, at which point theanimals are necropsied 4 hours after am administration. The colon lengthand weight is recorded and used as a secondary endpoint in the study asa measurement of colon oedema. The colon is then divided into sixcross-sections, four of which are used for histopathology scoring(primary endpoint) and two are homogenised for cytokine analysis. Datashown is the % inhibition of the induction window between naïve animalsand vehicle animals, where higher inhibition implies closer to thenon-diseased, naïve, phenotype.

Summary of In Vitro and In Vivo Screening Results

TABLE 1 Results from in vitro p38 MAPKα (Method 2), c-Src, Syk and GSK3α(Method 2) inhibition assays Test Compound IC50 Values for EnzymeInhibition (nM) Example No. p38 MAPKα c-Src Syk GSK3α 1 8560 >1,000 >10,000 2 380 24 50 >10,000 3 87 203 113 >10,000 4 — — — 539 5— — — 602 6 — — — 243 7 271 81 185 >10,000 8 — 22 31 2573 9 — —— >10,000 10 46 — — 1759 11 — — — >10,000 12 214 74 275 2,314 13 152 1661 6,398 14 273 37 203 5,440 15 67 16 40 3,588 16 148 21 348 >10,000 17— — — >10,000

TABLE 2 Results from cellular assays in d-U937 cells, PBMCs and HT29cells (the protocols for which are described by assays (a) to (d)above). Test IC₅₀ Values for Inhibition of Cytokine Release (nM)Compound dU937 cells PBMCs HT29 cells Example No. IL-8 TNFα IL-8 IL-2IFNγ IL-8 1 3.2 1.4 1.6 — — — 2 0.9 0.4 2.0 18.0 3.6 3.2 3 4.4 2.8 2.10.7 — 6.0 4 — — 0.5 — — — 5 — — 1.0 — — — 6 — — 0.6 — — — 7 — — 4.0138.8 21.8  — 8 — — 1.4 — — — 9 — — 7.6 — — — 10 — — 1.7 7.1 — — 11 — —10.8 — — — 12 1.2 — 2.1 171.4 2.6 3.7 13 0.5 — 1.7 58.8 1.3 1.7 14 1.8 —1.4 169.6 2.0 3.6 15 1.3 — 0.8 69.3 2.4 2.5 16 — — 17.7 — — — 17 — —30.4 — — —

The IC₅₀ for inhibition of TNFα release was also measured in PBMCs(using assay (b) above) for the compound of Example 1, and found to be2.5 nM.

As illustrated in Table 3 below, the compound of Examples 2 and 13 werealso screened in in vivo assay (iv) above, as conducted over 2 days.Histopathology analysis revealed that the compound of Examples 2 and 13displayed significant activity in this in vivo model of colonicinflammation. In particular, those compounds, when dosed orally both at5 mg/kg (or, for the compound of Example 2, at 1 and at 5 mg/kg),demonstrated marked improvements in ulcer grade and epithelial repaircompared to the vehicle control. In addition, the compound of Examples 2and 13 produced a marked reduction in inflammatory cell infiltrate inthe reticular and lamina propria zones.

TABLE 3 Summary of results from studies on TNBS-induced colitis in mice.TNBS Experiment LP no. Treatment group n Ulcer grade inflammation 1Non-diseased 6 0.2 ± 0.2 0.3 ± 0.2 1 TNBS + Vehicle 12 4.0 ± 0.5 3.9 ±0.3 1 TNBS + Budesonide 11 2.9 ± 0.6 2.5 ± 0.4 (2.5 mg/kg) 1 TNBS +Example 2 12 3.4 ± 0.6 2.7 ± 0.4 (1 mg/kg) 1 TNBS + Example 2 12 2.4 ±0.6 1.7 ± 0.4 (5 mg/kg) 2 Non-diseased 6 0.0 ± 0.0 0.2 ± 0.2 2 TNBS +Vehicle 24 4.4 ± 0.2 4.5 ± 0.2 2 TNBS + Example 13 12 3.0 ± 0.4 2.8 ±0.3 (1 mg/kg) 2 TNBS + Example 13 12 2.9 ± 0.5 2.3 ± 0.3 (5 mg/kg)

As illustrated in Table 4 below, the compounds of Examples 2 and 13 werealso screened in cellular assay (I), i.e., the ex-vivo human biopsymodel described above, where it demonstrated significantanti-inflammatory effects in biopsies from ulcerative colitis (UC)patients. In contrast to healthy volunteers, intestinal mucosal biopsiesfrom UC patients have been shown to spontaneously releasepro-inflammatory cytokines in vitro (Onken, J. E. et al., J ClinImmunol, 2008, 126(3): 345-352). Thus, the compound of Examples 2 and 13significantly inhibited cytokine (IL-11, IL-6 and IL-8) release comparedto the DMSO control when incubated, at 1 μg/mL, for 24 hours withbiopsies from ulcerative colitis patients.

TABLE 4 Summary of results from assays using intestinal mucosa biopsiesfrom the inflamed regions of the colon of various patients sufferingfrom ulcerative colitis (a form of IBD). Cytokine release from biopsiesof UC patients IL-1β IL-6 IL-8 Treatment group n release n release nrelease DMSO control 100% 100% 100% Example 2 (1 μg/mL) 3 20 ± 13 8 37 ±41 8 22 ± 21 Example 13 (1 μg/mL) 5 3 ± 3 5 37 ± 52 5 7 ± 8

ABBREVIATIONS

-   -   AcOH glacial acetic acid    -   aq aqueous    -   ATP adenosine-5′-triphosphate    -   BALF bronchoalveolar lavage fluid    -   BINAP 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl    -   br broad    -   BSA bovine serum albumin    -   CatCart® catalytic cartridge    -   CDI 1,1-carbonyl-diimidazole    -   COPD chronic obstructive pulmonary disease    -   d doublet    -   dba dibenzylideneacetone    -   DBU 1,8-diazabicyclo[5.4.0]undec-7-ene    -   DCM dichloromethane    -   DMAP 4-dimethylaminopyridine    -   DMF dimethylformamide    -   DMSO dimethyl sulfoxide    -   d-U937 cells PMA differentiated U-937 cells    -   (ES⁺) electrospray ionization, positive mode    -   Et ethyl    -   Et₃N triethylamine    -   EtOAc ethyl acetate    -   EtOH ethanol    -   FCS foetal calf serum    -   FRET fluorescence resonance energy transfer    -   GSK3α glycogen synthase kinase 3α    -   HBEC primary human bronchial epithelial cells    -   HPLC high performance liquid chromatography    -   hr hour(s)    -   HRP horseradish peroxidise    -   HRV human rhinovirus    -   ICAM-1 inter-cellular adhesion molecule 1    -   JNK c-Jun N-terminal kinase    -   LC liquid chromatography    -   LPS lipopolysaccharide    -   (M+H)⁺ protonated molecular ion    -   MAPK mitogen-activated protein kinase    -   MAPKAP-K2 mitogen-activated protein kinase-activated protein        kinase-2    -   Me methyl    -   MeCN acetonitrile    -   MeOH methanol    -   MHz megahertz    -   min minute(s)    -   MMAD mass median aerodynamic diameter    -   MOI multiplicity of infection    -   MTT 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide    -   MS mass spectrometry    -   m/z: mass-to-charge ratio    -   NMP N-methyl pyrrolodinone    -   NMR nuclear magnetic resonance (spectroscopy)    -   PBMC peripheral blood mononuclear cell    -   PBS phosphate buffered saline    -   Ph phenyl    -   PHA phytohaemagglutinin    -   PMA phorbol myristate acetate    -   p-TsOH 4-methylbenzenesulfonic acid (para-toluenesulfonic acid)    -   q quartet    -   rt room temperature    -   RP HPLC reverse phase high performance liquid chromatography    -   RSV respiratory syncytial virus    -   s singlet    -   sat saturated    -   SCX solid supported cation exchange (resin)    -   SDS sodium dodecyl sulphate    -   S_(N)Ar nucleophilic aromatic substitution    -   t triplet    -   T3P 1-propanephosphonic acid cyclic anhydride    -   TBAF tetrabutylammonium fluoride    -   TBDMS tert-butyldimethylsilyl    -   TCID₅₀ 50% tissue culture infectious dose    -   TEA triethylamine    -   THF tetrahydrofuran    -   TFA trifluoroacetic acid    -   TNFα tumor necrosis factor alpha

Prefixes n-, s-, i-, t- and tert- have their usual meanings: normal,secondary, iso, and tertiary.

What is claimed is:
 1. A compound of formula I,

wherein R¹ represents H or C₁₋₃ alkyl; R² and R³ independently representH or C₁₋₃ alkyl, or R² and R³ together combine to form C₂₋₃ alkylene; X¹and X² are both N, or X¹ is C and X² is either O or S; Ar is phenyl or a5- or 6-membered heteroaryl group containing one or more heteroatomsselected from the group consisting of N, O and S, which phenyl andheteroaryl groups are optionally substituted by one or more substituentsselected from the group consisting of halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl,C₁₋₄ alkoxy, hydroxy, amino and cyano; L is a direct bond or C₁₋₂alkylene; E represents: (a) H, halo, hydroxy, NR^(6a)R^(6b), cyano,C(O)OR^(6c), C(O)NR^(6d)R^(6e), SH, S(O)_(n)R⁸, S(O)₂NR^(6f)R^(6g), (b)C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₈ alkoxy, which latter fourgroups are optionally substituted by one or more substituents selectedfrom the group consisting of halo and NR^(7a)R^(7b), (c) C₃₋₈cycloalkyl, Het¹ or Ar¹, which latter three groups are optionallysubstituted by one or more substituents selected from the groupconsisting of halo, hydroxy and C₁₋₃ alkyl; R^(6a) to R^(6g)independently represent H or C₁₋₄ alkyl, or any one or more of the pairsR^(6a) and R^(6b), R^(6d) and R^(6e), and R^(6f) and R^(6g), when takentogether with the N-atom to which each pair is attached, form asaturated 4- to 7-membered heterocyclic group, which heterocyclic groupcontains one N atom (the atom to which the pairs of substituents areattached) and, optionally, one or more further heteroatoms selected fromthe group consisting of O, S and N, and which heterocyclic group isoptionally substituted by one or more C₁₋₂ alkyl groups; R^(7a) andR^(7b), independently on each occurrence, represent H or C₁₋₄ alkyl, or,together with the N-atom to which they are attached, form a 5- to7-membered heterocyclic group that is fully saturated, partiallyunsaturated or fully aromatic and which heterocyclic group contains oneN atom (the atom to which R^(7a) and R^(7b) are attached) and,optionally, one or more further heteroatoms selected from the groupconsisting of O, S and N, and which heterocyclic group is optionallysubstituted by one or more substituents selected from the groupconsisting of halo, hydroxy, oxo, C₁₋₄ alkyl and C₁₋₄ alkoxy; R⁸represents C₁₋₄ haloalkyl, C₁₋₄ alkyl, C₃₋₈ cycloalkyl or Ar², whichlatter three groups are optionally substituted by one or moresubstituents selected from the group consisting of halo, hydroxy andC₁₋₃ alkyl; Ar¹ and Ar² independently represent C₆₋₁₄ carbocyclic arylgroups, which groups may be monocyclic, bicyclic or tricyclic and whichgroups contain at least one ring which is fully aromatic, n is 0, 1 or2; R⁴ and R⁵ are each independently C₁₋₃ alkyl, C₁₋₃ haloalkyl, cyano orhalo, or R⁴ and R⁵ together combine to form C₃₋₅ alkylene or C₃₋₅alkenylene, which latter two groups are optionally substituted by one ormore substituents selected from the group consisting of C₁₋₃ alkyl, C₁₋₃haloalkyl, cyano and halo, or R⁴ and R⁵, together with the C-atoms towhich they are attached, form a fused phenyl or Het² ring, which lattertwo rings are optionally substituted by one or more substituentsselected from the group consisting of C₁₋₃ alkyl, C₁₋₃ haloalkyl, cyanoand halo; Het¹ and Het² independently represent 5- to 7-memberedheterocyclic groups that are fully saturated, partially unsaturated orfully aromatic, which heterocyclic groups contain one or moreheteroatoms selected from the group consisting of N, O and S; one of Aand A¹ represents N and the other represents CH, or both of A and A¹represent CH; G represents phenyl optionally substituted by one or moreY¹ or Het³ optionally substituted by one or more Y²; G¹ represents H; orG and G¹ together combine to form C₃₋₆ alkylene optionally substitutedby one or more substituents selected from the group consisting of halo,hydroxy and C₁₋₃ alkyl, which latter group is optionally substituted byone or more halo atoms or by hydroxy; each Y¹ is independently selectedfrom the group consisting of: halo, hydroxy, cyano, SF₅, —OC(O)NH₂,P(O)R^(9a)R^(9b), J¹-N(R^(9c))R^(9d), J²-S(O)₂R^(9e),J³-[CH₂(CH₂)₀₋₁CH₂—O]₂₋₈—R^(9f), —C≡C—R^(9g), —N═S(O)R^(9h)R^(9i),Het^(a), and C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₁₋₆ alkoxy, C₃₋₆ cycloalkoxy,—S(O)₀₋₁—C₁₋₆ alkyl and —S(O)₀₋₁—C₃₋₆ cycloalkyl which latter six groupsare optionally substituted by one or more substituents selected from thegroup consisting of halo, hydroxy, C₁₋₃ alkyl, C₁₋₃ alkoxy and C₃₋₆cycloalkyl; each Y² independently represents oxo or Y¹; J¹ represents adirect bond, —C(O)— —[C(O)]_(p)—C₁₋₈ alkylene, —C(O)NR^(10a)—CH₂—[C₁₋₇alkylene]-, -Q¹-CH₂—[C₁₋₅ alkylene]-, the alkylene parts of which latterfour groups are optionally substituted by one or more substituentsselected from the group consisting of halo, C₁₋₃ alkyl and hydroxy; J²represents a direct bond, —O—, —NH— C₁₋₆ alkylene or -Q²-CH₂—[C₁₋₅alkylene]-, the alkylene parts of which latter two groups are optionallysubstituted by one or more substituents selected from the groupconsisting of halo, C₁₋₃ alkyl and hydroxy; J³ represents —O— orS(O)₀₋₂; Q¹ and Q² independently represent O or S(O)₀₋₂; p represents 0or 1; R^(9a) and R^(9b) independently represent C₁₋₃ alkyl or C₁₋₃alkoxy, or R^(9a) and R^(9b) together combine to form C₄₋₆ alkylene;R^(9c) and R^(9d) independently represent H or C₁₋₈ alkyl, which lattergroup is optionally substituted by R^(10b) and/or one or moresubstituents selected from the group consisting of halo and hydroxy; orR^(9c) and R^(9d), together with the N-atom to which they are attached,form a 4- to 7-membered heterocyclic group that is fully saturated,partially unsaturated or fully aromatic and which heterocyclic groupcontains one N atom (the atom to which R^(9c) and R^(9d) are attached)and, optionally, one or more further heteroatoms selected from the groupconsisting of O, S and N, and which heterocyclic group is optionallysubstituted by one or more substituents selected from the groupconsisting of halo, hydroxy, oxo, C₁₋₄ alkyl and C₁₋₄ alkoxy; R^(9e)represents C₁₋₆ alkyl, C₃₋₆ cycloalkyl or phenyl, which latter threegroups are optionally substituted by one or more substituents selectedfrom the group consisting of halo, hydroxy, C₁₋₃ alkyl, C₁₋₃ alkoxy andC₃₋₆ cycloalkyl; R^(9f), R^(9g), R^(9h) and R^(9i) independentlyrepresent C₁₋₄ alkyl optionally substituted by one or more halo atoms,or R^(9f) and R^(9g) independently represent H; R^(10a) represents H orC₁₋₃ alkyl optionally substituted by one or more halo atoms; R^(10b)represents C₁₋₄ alkoxy, S—C₁₋₄ alkyl, phenyl or Het⁴, which latter twogroups are optionally substituted by one or more substituents selectedfrom the group consisting of halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄alkoxy, hydroxy, amino and cyano; Het³ represents a 5- to 10-memberedheteroaromatic group, which group is monocyclic or bicyclic and containsat least one carbocyclic or heterocyclic ring that is fully aromatic,and which group contains one or more heteroatoms selected from the groupconsisting of N, O and S; Het⁴ represents a 4- to 10-memberedheterocyclic group that is fully saturated, partially unsaturated orfully aromatic, which heterocyclic group contains one or moreheteroatoms selected from the group consisting of N, O and S; Het^(a)represents a 5- or 6-membered heterocyclic group that is fullysaturated, partially unsaturated or fully aromatic, which group containsone or more heteroatoms selected from the group consisting of N, O andS, and which group is optionally substituted by one or more substituentsselected from the group consisting of halo, hydroxy, C₁₋₃ alkyl, C₁₋₃alkoxy and C₃₋₆ cycloalkyl, or a pharmaceutically acceptable salt,solvate or isotopic derivative thereof.
 2. A compound as claimed inclaim 1 which is a compound of formula Ia,

wherein R¹ represents H or C₁₋₂ alkyl; R² and R³ independently representH or C₁₋₂ alkyl, or R² and R³ together combine to form C₂ alkylene; Arepresents CH or N; A² represents CH or N; R⁴ and R⁵ are both halo, orR⁴ and R⁵, together with the C-atoms to which they are attached, form afused phenyl ring; R^(a) represents C₁₋₂ alkyl or C₁₋₂ alkoxy, whichlatter two groups are optionally substituted by one or more halo atoms,or R^(a) represents C₁₋₂ alkyl or C₂ alkoxy, which latter two groups aresubstituted by NR^(7a)R^(7b); R^(7a) and R ^(7b) both represent C₁₋₂alkyl or, together with the N-atom to which they are attached, form a 5-or 6-membered heterocyclic group that is fully saturated and whichheterocyclic group contains one N atom (the atom to which R^(7a) andR^(7b) are attached) and, optionally, one further heteroatom selectedfrom the group consisting of O, S and N, and which heterocyclic group isoptionally substituted by one or more substituents selected from thegroup consisting of halo, hydroxy, oxo, C₁₋₄ alkyl and C₁₋₄ alkoxy; A³and A⁴ both represent CH, or one of A³ and A⁴ represents N and the otherrepresents CH; R^(b), R^(c) and R^(d) independently represent H, halo,hydroxy, —C≡C—H, C₁₋₄ alkylene-N(R^(9c))R^(9d), —C(O)NH—CH₂—[C₁₋₃alkylene]-N(R^(9c))R^(9d), -Q¹-CH₂—[C₁₋₃ alkylene]-N(R^(9c))R^(9d),—O—[CH₂CH₂O]₂₋₇—R^(9f), C₁₋₄ alkyl, C₁₋₄ alkoxy or C(O)NHC₁₋₄ alkyl,which latter three groups are optionally substituted by one or more haloatoms, or R^(b) and R^(c), together with the C-atoms to which they areattached, form a fused, 5- or 6-membered heteroaromatic or heterocyclicring, which ring: (i) contains one to three heteroatoms selected fromthe group consisting of N, O and S; and (ii) is optionally substitutedby one or more substituents selected from the group consisting of H,halo, hydroxy, oxo, amino, C₁₋₂ alkyl and C₁₋₂ alkoxy, which latter twogroups are optionally substituted by one or more halo atoms; R^(9c) andR^(9d) both represent C₁₋₂ alkyl or, together with the N-atom to whichthey are attached, form a 5- or 6-membered heterocyclic group that isfully saturated and which heterocyclic group contains one N atom (theatom to which R^(9c) and R^(9d) are attached) and, optionally, onefurther heteroatom selected from the group consisting of O, S and N, andwhich heterocyclic group is optionally substituted by one or moresubstituents selected from the group consisting of halo, hydroxy, oxo,C₁₋₄ alkyl and C₁₋₄ alkoxy; and R^(9f) represents H or methyl, or apharmaceutically acceptable salt, solvate or isotopic derivativethereof.
 3. A compound as claimed in claim 2, which is a compound offormula Ib,

or a pharmaceutically acceptable salt, solvate or isotopic derivativethereof, wherein R¹ to R⁵, A, A², A³, A⁴ and R^(a) to R^(d) are asdefined in claim
 2. 4. A compound as claimed in claim 2 which is acompound of formula Ic, Id or Ie,

or a pharmaceutically acceptable salt, solvate or isotopic derivativethereof, wherein: R¹ to R⁵, A, A² and R^(a) are as defined in claim 2;R^(c2) and R^(d2) are as defined above for R^(c) and R^(d) in claim 2;R^(d1) is as defined above for R^(d) in claim 2; and A^(x) represents CHor N.
 5. A compound as claimed in claim 2, wherein R¹ is H and R² and R³both represent methyl.
 6. A compound as claimed in claim 2, wherein A²represents CH.
 7. A compound as claimed in claim 2, wherein R^(a)represents methyl.
 8. A compound as claimed in claim 4, wherein R^(d1)represents H or methyl.
 9. A compound as claimed in claims 4, wherein:(i) R^(c2) represents H and R^(d2) represents —O—[CH₂CH₂O]₂₋₇—CH₃,—C(O)NH—CH₂CH₂—N(R^(9c))R^(9d) or —O—CH₂CH₂—N(R^(9c))R^(9d), (ii) bothof R^(c2) and R^(d2) represent H, or (iii) R^(c2) represents CH₃,—C≡C—H, —CF₃, —OCF₃ or —OCH₃ and R^(d2) represents —O—[CH₂CH₂O]₂₋₇—CH₃,—C(O)NH—CH₂CH₂—N(R^(9c))R^(9d) or —O—CH₂CH₂—N(R^(9c))R^(9d).
 10. Acompound as claimed in claim 1, wherein NR^(9c)R^(9d) representsdimethylamino or morpholin-4-yl.
 11. A compound as claimed in claim 1,wherein R⁴ and R⁵, together with the C-atoms to which they are attached,form a fused phenyl ring.
 12. A compound as claimed in claim 1, whichcompound is selected from the group consisting of:1-(3-(2-methylbut-3-yn-2-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-(phenylamino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea;1-(4-((2-((7-methyl-1H-indazol-5-yl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)-3-(3-(2-methylbut-3-yn-2-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)urea;1-(3-(2-methylbut-3-yn-2-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((2-oxoindolin-6-yl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea;3-methoxy-5-((4-((4-(3-(3-(2-methylbut-3-yn-2-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-N-(2-morpholinoethyl)benzamide;1-(3-(2-methylbut-3-yn-2-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((3-(2-morpholinoethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea;1-(4-((2-((3-(2-(dimethylamino)ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)-3-(3-(2-methylbut-3-yn-2-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)urea;1-(3-(2-methylbut-3-yn-2-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-(phenylamino)pyridin-4-yl)oxy)naphthalen-1-yl)urea;1-(4-((2-((3-methoxy-5-(2-morpholinoethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)-3-(3-(2-methylbut-3-yn-2-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)urea;1-(2,3-dichloro-4-((2-((7-methyl-1H-indazol-5-yl)amino)pyrimidin-4-yl)oxy)phenyl)-3-(3-(2-methylbut-3-yn-2-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)urea;1-(4-((2-((6-(2-(dimethylamino)ethoxy)pyridin-2-yl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)-3-(3-(2-methylbut-3-yn-2-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)urea;1-(4-((2-((4-(2-(dimethylamino)ethoxy)pyridin-2-yl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)-3-(3-(2-methylbut-3-yn-2-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)urea;3-((4-((4-(3-(3-(2-methylbut-3-yn-2-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-N-(2-morpholinoethyl)-5-(trifluoromethyl)benzamide;1-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)-3-(3-(2-methylbut-3-yn-2-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)urea;3-((4-((4-(3-(3-(2-methylbut-3-yn-2-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-N-(2-morpholinoethyl)-5-(trifluoromethoxy)benzamide;3-ethynyl-5-((4-((4-(3-(3-(2-methylbut-3-yn-2-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-N-(2-morpholinoethyl)benzamide;1-(3-(2-methylbut-3-yn-2-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((6-(2-morpholinoethoxy)pyridin-2-yl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea; and1-(4-((2-((6-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)pyridin-2-yl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)-3-(3-(2-methylbut-3-yn-2-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)urea,or a pharmaceutically acceptable salt, solvate or isotopic derivativethereof.
 13. A compound as claimed in claim 1, which compound isselected from the group consisting of:1-(4-((2-((7-methyl-1H-indazol-5-yl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)-3-(3-(2-methylbut-3-yn-2-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)urea;and1-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)-3-(3-(2-methylbut-3-yn-2-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)urea,or a pharmaceutically acceptable salt, solvate or isotopic derivativethereof.
 14. A pharmaceutical formulation comprising a compound asdefined in claim 1, or pharmaceutically acceptable salt, solvate orisotopic derivative thereof, in admixture with a pharmaceuticallyacceptable adjuvant, diluent or carrier.
 15. A combination productcomprising (A) a compound as defined in claim 1, or pharmaceuticallyacceptable salt, solvate or isotopic derivative thereof, and (B) anothertherapeutic agent, wherein each of components (A) and (B) is formulatedin admixture with a pharmaceutically-acceptable adjuvant, diluent orcarrier.
 16. A method of treating inflammation, said method comprisingadministering to a subject an effective amount of: a compound as definedin claim 1; a pharmaceutical formulation comprising a compound asdefined in claim 1; a pharmaceutically acceptable salt of a compound asdefined in claim 1, or a solvate or isotopic derivative thereof, inadmixture with a pharmaceutically acceptable adjuvant, diluent orcarrier, or a combination product comprising: (A) a compound as definedin claim 1, or pharmaceutically acceptable salt, solvate or isotopicderivative thereof, and (B) another therapeutic agent, wherein each ofcomponents (A) and (B) is formulated in admixture with apharmaceutically-acceptable adjuvant, diluent or carrier, wherein theinflammation is a component in a disease selected from the groupconsisting of cystic fibrosis, pulmonary hypertension, lung sarcoidosis,idiopathic pulmonary fibrosis, Chronic Obstructive Pulmonary Disease(COPD), chronic bronchitis, emphysema), asthma, paediatric asthma,atopic dermatitis, allergic dermatitis, contact dermatitis or psoriasis,allergic rhinitis, rhinitis, sinusitis, conjunctivitis, allergicconjunctivitis, keratoconjunctivitis sicca (dry eye), glaucoma, diabeticretinopathy, macular oedema, diabetic macular oedema), central retinalvein occlusion (CRVO), dry and/or wet age related macular degeneration(AMD), post-operative cataract inflammation, uveitis, posterior uveitis,anterior uveitis, pan uveitis, corneal graft and limbal cell transplantrejection, gluten sensitive enteropathy (coeliac disease), eosinophilicesophagitis, intestinal graft versus host disease, Crohn's disease andulcerative colitis.
 17. The method according to claim 16, wherein thedisease is asthma or COPD.
 18. The method according to claim 16, whereinthe disease is uveitis, Crohn's disease or ulcerative colitis.
 19. Aprocess for the preparation of a compound of formula I according toclaim 1, which process comprises: (a) reaction of a compound of formulaII,

with a compound of formula III,

wherein one of Z¹ and Z² is a structural fragment of formula IV

and the other of Z¹ and Z² is a structural fragment of formula V

where E, L, Ar, X¹, X², R¹ to R⁵, A, A¹, G and G¹ are as defined inclaim 1; (b) reaction of a compound of formula IIa,

wherein Z¹ is as defined above, with a suitable azide-forming agent,which reaction is followed, without isolation, by thermal rearrangementof the intermediate acyl azide (of formula Z¹—C(O)—N₃) to provide, insitu, a compound of formula II, which compound is then reacted with acompound of formula Ill as defined above; (c) reaction of a compound offormula IIb,

wherein LG¹ represents a leaving group and Z¹ is as defined above, witha compound of formula III, as defined above; (d) reaction of a compoundof formula VI,

wherein LG² represents a leaving group and E, L, Ar, X¹, X², R¹ to R⁵, Aand A¹are as defined in claim 1, with a compound of formula VII,

wherein G and G¹ are as defined in claim 1; or (e) deprotection of anprotected derivative of a compound of formula I, wherein the protectedderivative bears a protecting group on an O— or N-atom of the compoundof formula I.